DOI: 10.1111/hiv.12119 _________________________________________________________________________________________________________________________ HIV Medicine

Transcription

DOI: 10.1111/hiv.12119
© 2014 British HIV Association
HIV Medicine (2014), 15 (Suppl. 1), 1–85
_________________________________________________________________________________________________________________________
British HIV Association guidelines for the treatment of
HIV-1-positive adults with antiretroviral therapy 2012
(Updated November 2013. All changed text is cast in yellow
highlight.)
NHS Evidence has accredited the process used by the
British HIV Association (BHIVA) to produce guidelines.
Accreditation is valid for five years from July 2012 and is
applicable to guidance produced using the processes
described in the British HIV Association (BHIVA) Guideline
Development Manual. More information on accreditation
can be viewed at www.nice.org.uk/accreditation
DOI: 10.1111/hiv.12119
British HIV Association guidelines for the treatment of
HIV-1-positive adults with antiretroviral therapy 2012
(Updated November 2013. All changed text is cast in
yellow highlight.)
Writing Group
Dr Ian Williams
Senior Lecturer, University College London and Honorary Consultant Physician, Central and North West London NHS
Foundation Trust (Chair)
Dr Duncan Churchill
Consultant Physician in HIV and Genitourinary Medicine, Brighton and Sussex University Hospitals NHS Trust (Vice
Chair)
Prof Jane Anderson
Consultant Physician and Director of the Centre for the Study of Sexual Health and HIV, Homerton University Hospital
NHS Foundation Trust, London
Dr Marta Boffito
Consultant Physician in HIV Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London
Prof Mark Bower
Professor of Oncology, Imperial College London and Consultant Physician in Medical Oncology, Chelsea and
Westminster Hospital NHS Foundation Trust, London
Mr Gus Cairns
UK Community Advisory Board representative/HIV treatment advocates network
Dr Kate Cwynarski
Consultant Physician in Haematology, Royal Free London NHS Foundation Trust
Dr Simon Edwards
Consultant Physician in HIV and Genitourinary Medicine, Central and North West London NHS Foundation Trust
(Section Lead)
Dr Sarah Fidler
Senior Lecturer in HIV and Genitourinary Medicine, Imperial College School of Medicine at St Mary’s, London
Dr Martin Fisher
Consultant Physician in HIV and Genitourinary Medicine, Brighton and Sussex University Hospitals NHS Trust (Section
Lead)
Dr Andrew Freedman
Reader in Infectious Diseases and Honorary Consultant Physician, Cardiff University School of Medicine
Prof Anna Maria Geretti
Professor of Virology and Infectious Diseases, Institute of Infection and Global Health, University of Liverpool
1
2 BHIVA Writing Group
Dr Yvonne Gilleece
Consultant Physician in HIV and Genitourinary Medicine, Brighton and Sussex University Hospitals NHS Trust
Prof Rob Horne
Professor of Behavioural Medicine, Head of Department of Practice and Policy and Director of Centre for Behavioural
Medicine, University College London
Prof Margaret Johnson
Professor in HIV Medicine and Clinical Director of HIV/AIDS Services, Royal Free London NHS Foundation Trust
Prof Saye Khoo
Honorary Consultant Physician in Infectious Diseases and Professor of Translational Medicine, University of Liverpool
Prof Clifford Leen
Consultant Physician in Infectious Diseases, Western General Hospital, Edinburgh and Honorary Professor in Infectious
Diseases, Edinburgh University
Mr Neal Marshall
Specialist HIV Pharmacist, Royal Free London NHS Foundation Trust
Dr Mark Nelson
Consultant Physician, Chelsea and Westminster Hospital NHS Foundation Trust, London
Dr Chloe Orkin
Consultant Physician and Lead for HIV Research, Barts Health NHS Trust, London
Dr Nicholas Paton
Senior Clinical Scientist, Medical Research Council Clinical Trials Unit, London
Prof Andrew Phillips
Professor of Epidemiology, University College London
Dr Frank Post
Senior Lecturer, King’s College London and Honorary Consultant Physician in Infectious Diseases, King’s College
Hospital NHS Foundation Trust, London
Dr Anton Pozniak
Consultant Physician, Chelsea and Westminster Hospital NHS Foundation Trust and Honorary Senior Lecturer, Imperial
College London
Prof Caroline Sabin
Professor of Medical Statistics and Epidemiology, University College London
Mr Roy Trevelion
UK Community Advisory Board representative/HIV treatment advocates network
Dr Andrew Ustianowski
Consultant in Infectious Diseases and Tropical Medicine and Associate Clinical Director, North Manchester General
Hospital
BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 3
Dr John Walsh
Consultant Physician in HIV and Sexual Health, Imperial College Healthcare NHS Trust, London
Dr Laura Waters
Consultant Physician in HIV and Genitourinary Medicine, Central and North West London NHS Foundation Trust
Dr Edmund Wilkins
Consultant Physician in Infectious Diseases and Director of the HIV Research Unit, North Manchester General Hospital
(Section Lead)
Dr Alan Winston
Consultant Physician, Imperial College Healthcare NHS Trust and Senior Lecturer in HIV and Genitourinary Medicine,
Imperial College London
Dr Mike Youle
Director of HIV Clinical Research, Royal Free London NHS Foundation Trust
Table of contents
1.0 Introduction
1.1 Scope and purpose
1.2 Methodology
1.2.1 Guideline development process
1.2.2 Patient involvement
1.2.3 GRADE
1.2.4 Good practice points
1.2.5 Dissemination and implementation
1.2.6 Guideline updates and date of next review
1.3 Treatment aims
1.4 Resource use
1.5 Implications for research
1.6 References
2.0 Recommendations and auditable outcomes
2.1 Recommendations (GRADE)
2.1.1 Patient involvement in decision making (Section 3)
2.1.2 When to start (Section 4)
2.1.3 What to start (Section 5)
2.1.4 Supporting patients on therapy (Section 6)
2.1.5 Managing virological failure (Section 7)
2.1.6 Antiretroviral therapies in specific populations (Section 8)
2.2 Summary of auditable measures
3.0 Patient involvement in decision-making
3.1 Recommendations
3.2 Rationale
3.3 References
4.0 When to start
4.1 Chronic infection
4.1.1 Recommendations
4.1.2 Rationale
4.1.3 References
4.2 Patients presenting with AIDS or a major infection
4.2.1 Recommendation
4.2.2 Rationale
4.2.3 References
4.3 Treatment of primary HIV infection
4.3.2 Rationale
4.3.3 References
4.4 Treatment to reduce transmission
4.4.2 Rationale
4.4.3 References
5.0 What to start
5.1 Summary recommendations
5.1.1 Summary of auditable measures
5.2 Introduction
5.3 Which nucleoside reverse transcriptase inhibitor backbone
5.3.2 Rationale
5.3.3 Not recommended
5.3.4 References
5.4 Which third agent
5.4.2 Rationale
5.4.4 References
5.5 Novel antiretroviral therapy strategies
5.5.2 Rationale
5.5.3 Reference
5.5.5 Rationale
5.5.6 References
6.0 Supporting patients on therapy
6.1 Adherence
6.1.1 Interventions to increase adherence to treatment
6.1.2 Should the choice of first-line antiretroviral therapy combination be affected by risk of non-adherence?
6.1.3 Dosing frequency
6.1.4 Fixed-dose combinations
6.1.5 References
6.2 Pharmacology
6.2.1 Drug interactions
6.2.2 Therapeutic drug monitoring
6.2.3 Stopping therapy: pharmacological considerations
6.2.4 Switching therapy: pharmacological considerations
6.2.5 References
6.3 Switching antiretroviral therapy in virological suppression
6.3.1 Introduction
6.3.2 Switching antiretrovirals in combination antiretroviral therapy
6.3.3 Protease inhibitor monotherapy
6.4 Stopping therapy
6.4.2 Rationale
6.4.3 References
7.0 Managing virological failure
7.1 Introduction
7.2 Blips, low-level viraemia and virological failure
7.2.2 Rationale
7.3 Patients with no or limited drug resistance
7.3.2 Rationale
7.4 Patients with triple-class (non-nucleoside reverse transcriptase inhibitor, nucleoside reverse transcriptase inhibitor, protease inhibitor) virological failure with or without triple-class resistance
7.4.2 Rationale
7.5 Patients with limited or no therapeutic options when a fully viral suppressive regimen cannot be constructed
7.5.2 Rationale
7.6 References
8.0 Antiretroviral therapy in specific populations
8.1 HIV with tuberculosis coinfection
8.1.1 When to start antiretroviral therapy
8.1.2 What to start
8.1.3 References
8.2 HIV and viral hepatitis coinfection
8.2.1 Introduction
8.2.2 Hepatitis B
8.2.3 Hepatitis C
8.2.4 References
8.3 HIV-related cancers
8.3.2 When to start antiretroviral therapy: AIDS-defining malignancies
8.3.3 When to start antiretroviral therapy: non-AIDS-defining malignancies
8.3.4 What to start
8.3.5 References
8.4 HIV-associated neurocognitive impairment
8.4.1 Introduction
8.4.3 What to start
8.4.4 Modification of antiretroviral therapy
8.4.5 References
8.5 Chronic kidney disease
8.5.2 What to start
8.5.3 References
8.6 Cardiovascular disease
8.6.1 Introduction
8.6.2 Definition and assessment of cardiovascular disease risk
8.6.4 What to start
8.6.5 References
8.7 Women
8.7.1 Introduction
8.7.2 When to start
8.7.3 What to start
8.7.4 HIV-positive women experiencing virological failure
8.7.5 References
9.0 Acknowledgements
9.1 Conflicts of interest statements
10.0 List of abbreviations
11.0 List of appendices
Appendix 1: Summary modified GRADE system
Appendix 2: Literature search
A2.1 Questions and PICO criteria
A2.2 Search protocols
Appendix 3: GRADE tables
A3.1 Choice of nucleoside reverse transcriptase inhibitor backbone
A3.2 Choice of third agent
A3.3 Protease inhibitor monotherapy
Appendix 4: BHIVA Treatment Guideline update 2013
1.0 Introduction
1.1 Scope and purpose
The overall purpose of these guidelines is to provide guidance
on best clinical practice in the treatment and management of
adults with HIV infection with antiretroviral therapy (ART).
The scope includes: (i) guidance on the initiation of ART in
those previously naïve to therapy; (ii) support of patients on
treatment; (iii) management of patients experiencing virological failure; and (iv) recommendations in specific patient
populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals
directly involved with and responsible for the care of adults
with HIV infection and at community advocates responsible
for promoting the best interests and care of HIV-positive
adults. They should be read in conjunction with other published BHIVA guidelines.
1.2 Methodology
1.2.1 Guideline development process
BHIVA revised and updated the association’s guideline
development manual in 2011 [1]. BHIVA has adopted the
modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for the assessment, evaluation and grading of evidence and development
of recommendations [2,3]. Full details of the guideline
development process, including conflict of interest policy,
are outlined in the manual.
The scope, purpose and guideline topics were agreed by
the Writing Group. Questions concerning each guideline
topic were drafted and a systematic literature review
undertaken by an information scientist. Details of the
search questions and strategy (including the definition of
populations, interventions and outcomes) are outlined in
Appendix 2. BHIVA adult ART guidelines were last published in 2008 [4]. For the 2012 guidelines the literature
search dates were 1 January 2008 to 16 September 2011
and included MEDLINE, EMBASE and the Cochrane library.
Abstracts from selected conferences (see Appendix 2) were
searched between 1 January 2009 and 16 September 2011.
For each topic and healthcare question, evidence was identified and evaluated by Writing Group members with
expertise in the field. Using the modified GRADE system
(Appendix 1), panel members were responsible for assessing and grading the quality of evidence for predefined
outcomes across studies and developing and grading the
strength of recommendations. An important aspect of
evaluating evidence is an understanding of the design and
analysis of clinical trials, including the use of surrogate
marker data.
Limited further searches concerning specific third agents
(rilpivirine [RPV] and elvitegravir [ELV]/cobicistat [COBI])
covering the period from September 2011 were carried out
in 2013.
For a number of questions, GRADE evidence profile and
summary of findings tables were constructed, using predefined and rated treatment outcomes (Appendix 3), to help
achieve consensus for key recommendations and aid transparency of the process. Before final approval by the Writing
Group, the guidelines were published online for public consultation and an external peer review was commissioned.
1.2.2 Patient involvement
BHIVA views the involvement of patient and community
representatives in the guideline development process as
essential. The Writing Group included two patient representatives appointed through the UK HIV Community Advisory Board (UK CAB) who were involved in all aspects of the
guideline development process. In addition, two meetings
with patients and community representatives were held to
discuss and receive feedback and comment on the proposed
guideline recommendations. The first was held before the
Writing Group’s consensus meeting and the second as part
of the public consultation process.
1.2.3 GRADE
The GRADE Working Group [3] has developed an approach
to grading evidence that moves away from initial reliance
on study design to consider the overall quality of evidence
across outcomes. BHIVA has adopted the modified GRADE
system for its guideline development.
The advantages of the modified GRADE system are (i) the
grading system provides an informative, transparent
summary for clinicians, patients and policy makers by
combining an explicit evaluation of the strength of the
recommendation with a judgement of the quality of the
evidence for each recommendation, and (ii) the two-level
grading system of recommendations has the merit of simplicity and provides clear direction to patients, clinicians
and policy makers.
A Grade 1 recommendation is a strong recommendation
to do (or not do) something, where the benefits clearly
outweigh the risks (or vice versa) for most, if not all
patients. Most clinicians and patients should and would
want to follow a strong recommendation unless there is a
clear rationale for an alternative approach. A strong recommendation usually starts with the standard wording ‘we
recommend’.
A Grade 2 recommendation is a weaker or conditional
recommendation, where the risks and benefits are more
closely balanced or are more uncertain. Most clinicians and
patients would want to follow a weak or conditional recommendation but many would not. Alternative approaches
or strategies may be reasonable depending on the individual patient’s circumstances, preferences and values. A
weak or conditional recommendation usually starts with
the standard wording ‘we suggest’.
The strength of a recommendation is determined not only
by the quality of evidence for defined outcomes but also
the balance between desirable and undesirable effects of a
treatment or intervention, differences in values and preferences and, where appropriate, resource use. Each recommendation concerns a defined target population and is
actionable.
The quality of evidence is graded from A to D and for the
purpose of these guidelines is defined as the following.
Grade A evidence means high-quality evidence that
comes from consistent results from well-performed randomized controlled trials (RCTs), or overwhelming evidence of some other sort (such as well-executed
observational studies with consistent strong effects and
exclusion of all potential sources of bias). Grade A
implies confidence that the true effect lies close to the
estimate of the effect.
Grade B evidence means moderate-quality evidence from
randomized trials that suffer from serious flaws in conduct,
inconsistency, indirectness, imprecise estimates, reporting
bias, or some combination of these limitations, or from
other study designs with special strengths such as observational studies with consistent effects and exclusion of
most potential sources of bias.
Grade C evidence means low-quality evidence from controlled trials with several very serious limitations or observational studies with limited evidence on effects and
exclusion of most potential sources of bias.
Grade D evidence on the other hand is based only on
case studies, expert judgement or observational studies
with inconsistent effects and a potential for substantial
bias, such that there is likely to be little confidence in the
effect estimate.
1.2.4 Good practice points
In addition to graded recommendations, the BHIVA Writing
Group has also included good practice points (GPP), which
are recommendations based on the clinical judgement and
experience of the working group. GPPs emphasize an area
of important clinical practice for which there is not, nor is
there likely to be, any significant research evidence. They
address an aspect of treatment and care that is regarded as
such sound clinical practice that healthcare professionals
are unlikely to question it and where the alternative recommendation is deemed unacceptable. It must be emphasized that GPPs are not an alternative to evidence-based
recommendations.
1.2.5 Dissemination and implementation
The following measures have/will be undertaken to disseminate and aid implementation of the guidelines:
• E-publication on the BHIVA website and the journal HIV
Medicine.
• Publication in HIV Medicine.
• Shortened version detailing concise summary of recommendations.
• E-learning module accredited for CME.
• Educational slide set to support local and regional educational meetings.
• National BHIVA audit programme.
1.2.6 Guideline updates and date of next review
The guidelines will be next fully updated and revised in
2014. However, the Writing Group will continue to meet
regularly to consider new information from high-quality
studies and publish amendments and addendums to the
current recommendations before the full revision date
where this is thought to be clinically important to ensure
continued best clinical practice.
1.3 Treatment aims
The primary aim of ART is the prevention of the mortality and morbidity associated with chronic HIV infection at low cost of drug toxicity. Treatment should
improve the physical and psychological well-being of
people living with HIV infection. The effectiveness and
tolerability of ART has improved significantly over the
last 15 years. The overwhelming majority of patients
attending HIV services in the UK and receiving ART
experience long-term virological suppression and good
treatment outcomes [5], which compare very favourably
with other developed countries.
Recent data have shown that life expectancy in the UK of
someone living with HIV infection has improved significantly over recent years but is still about 13 years less than
that of the UK population as a whole [6]. For someone aged
20 years starting ART, life expectancy increased from 30.0
to 45.8 years from 1996–1999 to 2006–2008. The impact of
starting ART late is large, with up to 15 years of reduced
life expectancy if ART is started later than the current
BHIVA guidelines recommend. Other data have shown that
for HIV-positive men who have sex with men living in a
developed country with extensive access to HIV care and
assuming a high rate of HIV diagnosis, the projected life
expectancy was 75 years [7]. The authors concluded that
the greatest risk of excess mortality is due to delays in HIV
diagnosis. Decreasing late diagnosis, starting ART earlier at
recommended CD4 cell count levels, maintaining patients
in care and reducing long-term drug toxicity and nonAIDS co-morbidities are crucial to further improving life
expectancy and the well-being of people living with HIV
infection.
A further aim of treatment is the reduction in sexual
transmission of HIV and for some patients may be the
primary aim. The use of ART to prevent mother-to-child
transmission is universally accepted and best practice is
addressed in the BHIVA guidelines for the management of
HIV infection in pregnant women [8]. Recently, the size of
the effect of ART on reducing the risk of sexual transmission of HIV has been estimated at >95% [9,10]. At a
population level, ART may be potentially important in
reducing the incidence of HIV infection. ART is usually
started for the health benefit of the individual, but in
certain circumstances, it may be beneficial to start ART to
primarily reduce the risk of onward sexual transmission of
HIV.
1.4 Resource use
ART is extremely cost-effective and compares favourably
with the cost of management of many other chronic diseases. Estimates of the cost-effectiveness of ART have been
assessed in studies in North America and Europe [11-13].
Their findings have been consistent with an estimated
incremental cost-effectiveness ratio of about US$20 000
per quality adjusted life year for combination ART compared with no therapy based on drug costs and treatment
patterns in the USA and Europe [14].
The number of people living with HIV in the UK continues to increase and by the end of 2010 was estimated to
be 91 500 of whom 24% were undiagnosed. Of those
diagnosed, 69 400 accessed HIV services in 2010 of whom
82% were on ART [5]. With ongoing HIV transmission,
increased HIV testing and a reduction in the undiagnosed
fraction, the number of people diagnosed with HIV and
accessing HIV services will continue to increase. It has been
estimated that the annual population treatment and care
costs rose from £104 million in 1997 to £483 million in
2006, rising to a projected annual cost of £721 million in
2013 [15]. It is likely this estimated projected cost is an
overestimate due to various factors, including earlier diagnosis and a lower proportion of patients with symptoms.
However, in the current economic climate containing and
reducing annual costs without affecting the current high
standards of care and treatment outcomes will be an
immense challenge to commissioners, healthcare professionals and patients alike. A collaborative approach is
required.
In the UK, higher annual treatment and care costs have
been associated with late diagnosis and initiation of ART at
lower CD4 cell counts than the BHIVA guidelines recommend [16,17]. In addition to earlier diagnosis and initiation
of ART, reducing inpatient episodes, decreasing drug toxicity, preventing HIV-associated co-morbidities and innovations in models of care are likely to have a beneficial
effect on annual costs. However, the cost of antiretroviral
(ARV) drugs remains the major factor contributing to treatment and care costs. With the future availability of generic
drugs and the introduction of a standard tariff for HIV
services (in England), clinicians and patients will be faced
with difficult choices about the value and benefit of different ARV drugs.
The BHIVA Writing Group recognizes that cost of drugs
is an important issue in the choice of ART regimens There
are limited cost-effectiveness data in the UK comparing
different ARV drugs and for this reason the Writing Group
did not include cost-effectiveness as an outcome in ART
comparisons. However, the Writing Group believes that
decreasing the risk of virological failure, drug resistance
and drug-associated toxicity are likely to have a beneficial impact on long-term cost-effectiveness and resource
use. In the setting of equivalent virological efficacy, determining the acceptable threshold at which differences in
the risk of toxicity, tolerability and convenience outweigh
differences in resource use and cost will be important.
These thresholds may differ among clinicians and patients
alike.
In developing the recommendations in these guidelines,
the Writing Group has taken into account differences in
critical treatment outcomes between different drug regimens in determining preferred and alternative treatment
regimens. The Writing Group recognizes and supports that
commissioning arrangements and local drug costs will and
should influence ART choice where outcomes, across a
range of clinical measures, are equivalent between individual drugs in the treatment of defined patient populations. The Writing Group, however, believes that reducing
treatment costs should not be at the cost of an increased
risk of poorer treatment outcomes and quality of care, not
least as these are likely to have a detrimental impact on
long-term cost.
1.5 Implications for research
In reviewing quality of evidence, guidelines will identify
areas of treatment and care where there is either an absence
of evidence or limited confidence in the size of effect to
influence choice of treatments or determine treatment and
management strategies. For this reason, it is not the intention of these guidelines to stifle clinical research but help
promote continued research with the aim to further improve
clinical care and treatment outcomes. The Writing Group
supports the development and provision of HIV clinical
trials within the UK and participation in a clinical trial
should be open and offered to patients where appropriate.
7 Nakagawa F, Lodwick RK, Smith CJ et al. Projected life
expectancy of people with HIV according to timing of
diagnosis. AIDS 2012; 26: 335–343.
8 Taylor GT, Clayden P, Dhar J et al. BHIVA guidelines for the
management of HIV infection in pregnant women 2012. HIV
Med 2012; 13 (Suppl. 2): 87–157.
9 Cohen MS, Chen YQ, McCauley M et al. Prevention of HIV-1
infection with early antiretroviral therapy. N Engl J Med
2011; 365: 493–505.
10 Attia S, Egger M, Muller M, Zwahlen M, Low N. Sexual
transmission of HIV according to viral load and
antiretroviral therapy: systematic review and meta-analysis.
AIDS 2009; 23: 1397–1404.
11 Sendi P, Butcher H, Harr T et al. Cost effectiveness of highly
active antiretroviral therapy in HIV infected patients: Swiss
1 BHIVA. Guideline development manual, 13 September 2011.
http://www.bhiva.org
HIV Cohort study. AIDS 1999; 13: 1115–1122.
12 Miners AH, Sabin CA, Trueman P et al. Assessing cost
effectiveness of highly active antiretroviral therapy for
adults with HIV in England. HIV Med 2001; 2: 52–58.
2 Guyatt GH, Oxman AD, Kunz R et al. Going from evidence
to recommendations. BMJ 2008; 336: 1049–1051.
13 Freedberg KA, Losina E, Weinstein MC et al. The cost
effectiveness of combination antiretroviral therapy in HIV
3 Development and Evaluation (Short GRADE) Working Group.
The grading of recommendations assessment. Available at
http://www.gradeworkinggroup.org (accessed April 2012).
disease. N Engl J Med 2001; 344: 824–831.
14 Yazdanpanah Y. Costs associated with combination
antiretroviral therapy in HIV infected persons. J Antimicrob
1.6 References
4 Gazzard B, on behalf of the BHIVA Treatment Guidelines
Chemother 2004; 53: 558–561.
Writing Group. British HIV Association guidelines for the
treatment of HIV-1-infected adults with antiretroviral
therapy 2008. HIV Med 2008; 9: 563–608.
15 Mandalia S, Mandalia R, Lo G et al. Rising population cost
for treating people living with HIV in the UK, 1997–2013.
PLoS ONE 2010; 5: e15677.
5 Health Protection Agency. HIV in the United Kingdom: 2011
report. Available at http://www.hpa.org.uk/HIV (accessed
April 2012).
doi:10.1371/journal.pone.0015677.
16 Beck EJ, Mandalia S, Sangha R et al. The cost effectiveness
of early access to HIV services and starting cART in the UK
1996–2008. PLoS ONE 2011; 6: e27830.
17 Beck EJ, Mandalia S, Lo G et al. Cost-effectiveness of early
6 May M, Gompels M, Delpech V et al. Impact of late
diagnosis and treatment on life expectancy in people with
HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ
2011; 343: d61016.
treatment with first-line NNRTI-based HAART regimens in
the UK, 1996–2006. PLoS ONE 2011; 6: e20200.
2.0 Recommendations and auditable outcomes
2.1 Recommendations (GRADE)
2.1.1 Patient involvement in decision making (Section 3)
3.1
We recommend patients are given the opportunity to be involved in making decisions about their
treatment.
GPP
2.1.2 When to start (Section 4)
2.1.2.1 Chronic infection
4.1
We recommend patients with chronic infection start ART if the CD4 cell count is ⱕ350 cells/mL: it is
important not to delay treatment initiation if the CD4 cell count is close to this threshold.
We recommend patients with the following conditions start ART:
• AIDS diagnosis [e.g. Kaposi sarcoma (KS)] irrespective of CD4 cell count.
• HIV-related co-morbidity, including HIV-associated nephropathy (HIVAN), idiopathic thrombocytopenic purpura, symptomatic HIV-associated neurocognitive (NC) disorders irrespective of CD4 cell
count.
• Coinfection with hepatitis B virus (HBV) if the CD4 cell count is ⱕ500 cells/mL (see Section 8.2.2
Hepatitis B).
• Coinfection with hepatitis C virus (HCV) if the CD4 cell count is ⱕ500 cells/mL (Section 8.2.3
Hepatitis C).
• Non-AIDS-defining malignancies requiring immunosuppressive radiotherapy or chemotherapy
(Section 8.3.2 When to start ART: non-AIDS-defining malignancies).
We suggest patients with the following conditions start ART:
• Coinfection with HBV if the CD4 cell count is >500 cells/mL and treatment of hepatitis B is indicated
(see Section 8.2.2 Hepatitis B).
2.1.2.2 Patients presenting with AIDS or a major infection
4.2
We recommend patients presenting with an AIDS-defining infection, or with a serious bacterial
infection and a CD4 cell count <200 cells/mL, start ART within 2 weeks of initiation of specific
antimicrobial chemotherapy.
2.1.2.3 Treatment of primary HIV infection
4.3
We recommend patients presenting with primary HIV infection (PHI) and meeting any one of the
following criteria start ART:
• Neurological involvement.
• Any AIDS-defining illness.
• Confirmed CD4 cell count <350 cells/mL.
2.1.2.4 Treatment to reduce transmission
4.4
We recommend the evidence that treatment with ART lowers the risk of transmission is discussed with
all patients, and an assessment of the current risk of transmission to others is made at the time of this
discussion.
We recommend following discussion, if a patient with a CD4 cell count >350 cells/mL wishes to start
ART to reduce the risk of transmission to partners, this decision is respected and ART is started.
2.1.3 What to start (Section 5)
5.1
We recommend therapy-naïve patients start ART containing two nucleos(t)ide reverse transcriptase
inhibitor (NRTIs) plus one of the following: a ritonavir-boosted protease inhibitor (PI/r), an NNRTI
or an integrase inhibitor (INI).
1A
1A
1C
1B
1C
1C
2B
1B
1D
1A
1C
GPP
GPP
1A
Summary recommendations for choice of ART:
Preferred
Alternative
NRTI backbone
Tenofovir and emtricitabine
Rilpivirine‡
Third agent
Atazanavir/ritonavir
Abacavir and lamivudine*‡
Darunavir/ritonavir
Lopinavir/ritonavir
Efavirenz
Fosamprenavir/ritonavir
Raltegravir
Nevirapine†
Elvitegravir/cobicistat
*Abacavir is contraindicated if HLA-B*57:01 positive.
†Nevirapine is contraindicated if baseline CD4 cell count is greater than 250/400 cells/mL in women/men.
‡Use recommended only if baseline VL <100 000 copies/mL: rilpivirine as a third agent, abacavir and lamivudine as NRTI
backbone.
The presence or future risk of co-morbidities and potential adverse effects need to be considered in the
choice of ARV drugs in individual patients.
2.1.3.1 Which nucleoside reverse transcriptase inhibitor backbone
5.3
We recommend therapy-naïve patients start combination ART containing tenofovir (TDF) and emtricitabine (FTC) as the NRTI backbone.
We suggest abacavir (ABC) and lamivudine (3TC) is an acceptable alternative NRTI backbone in
therapy-naïve patients who, before starting ART, have baseline viral load (VL) of ⱕ100 000 copies/mL.
ABC must not be used in patients who are HLA-B*57:01 positive.
2.1.3.2 Which third agent
5.4
We recommend therapy-naïve patients start combination ART containing one of the following as the
third agent: atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), efavirenz (EFV), raltegravir
(RAL) or elvitegravir (ELV)/cobicistat (COBI).
We suggest that in therapy-naïve patients lopinavir/ritonavir (LPV/r) and fosamprenavir/ritonavir
(FPV/r) are acceptable alternative PIs, and nevirapine (NVP) is an acceptable alternative NNRTI.
2.1.3.3 Novel antiretroviral therapy strategies
5.5
We recommend against the use of PI monotherapy as initial therapy for treatment-naïve patients.
We recommend against the use of PI-based dual ART with a single NRTI, NNRTI, C–C chemokine
receptor type 5 (CCR5) receptor antagonist or INI as initial therapy for treatment-naïve patients.
1A
2A
1A
1A
2A
1C
1C
2.1.4 Supporting patients on therapy (Section 6)
2.1.4.1 Adherence
6.1.1
Interventions to increase adherence to treatment
We recommend adherence and potential barriers to it are assessed and discussed with the patient
whenever ART is prescribed or dispensed.
We recommend adherence support should address both perceptual barriers (e.g. beliefs and preferences)
and/or practical barriers (e.g. limitations in capacity and resources) to adherence.
GPP
GPP
2.1.4.2 Pharmacology
6.2.1
6.2.2
Drug interactions
We recommend that potential adverse pharmacokinetic interactions between ARV drugs and other
concomitant medications are checked before administration (with tools such as http://www.hivdruginteractions.org).
Therapeutic drug monitoring
We recommend against the unselected use of therapeutic drug monitoring (TDM).
GPP
GPP
6.2.3
Stopping therapy: pharmacological considerations
We recommend patients stopping ART containing an NNRTI in combination with an NRTI backbone
replace all drugs with a PI (LPV/r) for 4 weeks.
We recommend patients stopping a PI-containing regimen stop all drugs simultaneously and no
replacement is required.
1C
1C
2.1.4.3 Switching antiretroviral therapies in virological suppression
6.3.2
6.3.3
Switching antiretrovirals in combination antiretroviral therapy
We recommend in patients on suppressive ART regimens, consideration is given to differences in side
effect profile, drug–drug interaction (DDIs) and drug resistance patterns before switching any ARV
component.
We recommend, in patients with previous NRTI resistance mutations, against switching a PI/r to either
an NNRTI or an INI as the third agent.
Protease inhibitor monotherapy
We recommend continuing standard combination ART as the maintenance strategy in virologically
suppressed patients. There are insufficient data to recommend PI/r monotherapy in this clinical
situation.
2.1.4.4 Stopping therapy
6.4
We recommend against treatment interruption or intermittent therapy in patients stable on a virally
suppressive ART regimen.
GPP
1B
1C
1A
2.1.5 Managing virological failure (Section 7)
2.1.5.1 Blips, low-level viraemia and virological failure
7.2
In patients on ART:
A single VL 50–400 copies/mL preceded and followed by an undetectable VL is usually not a cause for
clinical concern.
We recommend a single VL >400 copies/mL is investigated further, as it is indicative of virological
failure.
We recommend in the context of repeated viral blips, resistance testing is attempted.
2.1.5.2 Patients with no or limited drug resistance
7.3
We recommend patients experiencing virological failure on first-line ART with wild-type (WT) virus
at baseline and without emergent resistance mutations at failure switch to a PI/r-based combination
ART regimen.
We recommend patients experiencing virological failure on first-line ART with WT virus at baseline
and limited emergent resistance mutations (including two-class NRTI/NNRTI) at failure switch to a new
PI/r-based regimen with the addition of at least one, preferably two, active drugs.
We recommend patients experiencing virological failure on first-line PI/r plus two-NRTI-based
regimen, with major protease mutations, switch to a new active PI/r with the addition of at least one,
preferably two, active agents of which one has a novel mechanism of action.
We recommend against switching a PI/r to an INI or an NNRTI as the third agent in patients with
historical or existing reverse transcriptase (RT) mutations associated with NRTI resistance or past
virological failure on NRTIs.
2.1.5.3 Patients with triple-class (non-nucleoside reverse transcriptase inhibitor, nucleoside reverse transcriptase
inhibitor, protease inhibitor) virological failure with or without triple-class resistance
7.4
We recommend patients with persistent viraemia and with limited options to construct a fully
suppressive regimen are discussed/referred for expert advice (or through virtual clinic referral).
GPP
1C
1D
1C
1C
1C
1B
GPP
We recommend patients with triple-class resistance switch to a new ART regimen containing at least
two and preferably three fully active agents with at least one active PI/r such as DRV/r or tipranavir/
ritonavir (TPV/r) and one agent with a novel mechanism (CCR5 receptor antagonist or integrase/fusion
inhibitor) with etravirine (ETV) an option based on viral susceptibility.
1C
2.1.5.4 Patients with limited or no therapeutic options when a fully viral suppressive regimen cannot be constructed
7.5
We recommend accessing newer agents through research trials, expanded access and named patient
GPP
programmes.
We suggest continuing/commencing NRTIs as this may contribute partial ARV activity to a regimen,
2C
despite drug resistance.
We recommend the use of 3TC or FTC to maintain a mutation at codon position 184 of the RT gene.
1B
We recommend against discontinuing or interrupting ART.
1D
We recommend against adding a single, fully active ARV because of the risk of further resistance.
1D
We recommend against the use of maraviroc (MVC) to increase the CD4 cell count in the absence of
1C
CCR5 tropic virus.
2.1.6 Antiretroviral therapy in specific populations (Section 8)
2.1.6.1 HIV with tuberculosis coinfection: when to start
8.1.1
Timing of initiation of ART during tuberculosis (TB) therapy
1B
CD4 cell count (cells/mL)
When to start highly active anti-retroviral therapy (HAART)
<100
As soon as practical within 2 weeks after starting TB therapy
100–350
As soon as practical, but can wait until after completing 2 months’ TB treatment, especially
when there are difficulties with drug interactions, adherence and toxicities
At physician’s discretion
>350
2.1.6.2 HIV with tuberculosis: what to start
8.1.2
We recommend EFV in combination with TDF and FTC as first-line ART in TB/HIV coinfection.
We recommend that when rifampicin is used with EFV in patients over 60 kg, the EFV dose is increased
to 800 mg daily. Standard doses of EFV are recommended if the patient weighs <60 kg.
We recommend that rifampicin is not used with either NVP or a PI/r.
We recommend that where effective ART necessitates the use of PI/r that rifabutin is used instead of
rifampicin.
1C
1C
1C
1C
2.1.6.3 HIV and viral hepatitis coinfection: summary of when to start recommendations
CD4 cell count
(cells/mL)
HBV requiring treatment*
HBV not requiring
treatment
HCV with immediate plan to
start HCV treatment*
HCV with no immediate
plan to start HCV
treatment
>500
Start ART in some
patients (2C)
(Include TDF and FTC)
Defer ART
Defer ART
Defer ART
ⱕ500
Start ART (1B)
(Include TDF and FTC)
Start ART (1B)
(Include
TDF and FTC)
350–500
Start ART after HCV treatment
commenced (1C)
<350
Start ART before HCV treatment
(1B)
Discuss with HIV and viral
hepatitis specialist
Start ART (1C)
*See BHIVA Guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus [1] for indications
to treat hepatitis B and C.
2.1.6.4 Hepatitis B: when to start
8.2.2.1
• We recommend patients with HIV and hepatitis B virus coinfection who have a CD4 cell count <500
cells/mL are treated with fully suppressive ART inclusive of anti-HBV active antivirals.
• We recommend patients with HIV and HBV coinfection who have a CD4 cell count ⱖ500 cells/mL
and who have an HBV-DNA ⱖ2000 IU/mL and/or evidence of more than minimal fibrosis (Metavir
ⱖF2) are treated with fully suppressive ART inclusive of anti-HBV active antivirals.
2.1.6.5 Hepatitis B: what to start
8.2.2.2
• We recommend TDF/FTC as part of a fully suppressive ART combination should be given to all
patients where HBV treatment is deemed necessary.
• We recommend neither 3TC nor FTC be used as the sole active drug against HBV in ART due to the
rapid emergence of HBV resistant to these agents.
• We recommend 3TC/FTC may be omitted from the ART regimen and tenofovir be given as the sole
anti-HBV active agent if there is clinical or genotypic evidence of 3TC/FTC-resistant HBV or HIV.
2.1.6.6 Hepatitis C: when to start antiretroviral therapy
8.2.3.1
• We recommend all patients with HIV and hepatitis C virus coinfection be assessed for HCV treatment.
• We suggest commencing ART when the CD4 cell count is greater than 500 cells/mL in all patients who
are not to commence HCV treatment immediately.
• We recommend commencing ART when the CD4 cell count is less than 500 cells/mL in all patients who
are not to commence anti-HCV treatment immediately.
• We recommend commencing ART to optimize immune status before anti-HCV therapy is initiated when
the CD4 cell count is between 350 and 500 cells/mL unless there is an urgent indication for anti-HCV
treatment when ART should be commenced as soon as the patient has been stabilized on HCV therapy.
• We recommend commencing ART to allow immune recovery before anti-HCV therapy is initiated when
the CD4 cell count is less than 350 cells/mL.
2.1.6.7 Hepatitis C: what to start
8.2.3.2
• We recommend if patients are commencing ART, and DAAs are not being considered, standard
first-line ART should be commenced.
• We recommend when DAAs are to be used there is careful consideration of possible DDIs (1C) and
current or archived HIV resistance. All drug interactions should be checked with an expert source
(e.g., www.hiv-druginteractions.org).
• We recommend if boceprevir is to be used, RAL with TDF plus FTC should be the treatment of choice
for those with wild-type HIV (1C): pharmacokinetic data would support ETV, RPV and MVC as
alternatives.
• We recommend if telaprevir is to be used either RAL or standard-dose ATV/r should be used (1C):
pharmacokinetic data would support ETV, RPV and MVC as alternatives. EFV may be used but the
telaprevir dose needs to be increased to 1125 mg tds.
• We suggest that if ABC is to be used with ribavirin, the ribavirin should be weight-based
dose-adjusted.
2.1.6.8 HIV-related cancers: when to start
8.3.1
We recommend starting ART in HIV-positive patients with KS.
We recommend starting ART in HIV-positive patients with non-Hodgkin lymphoma (NHL).
We suggest starting ART in HIV-positive patients with cervical cancer.
We recommend starting ART in HIV-positive patients who are commencing radiotherapy or chemotherapy for cervical cancer.
8.3.2
We suggest starting ART in HIV-positive patients with non-AIDS-defining malignancies (NADMs).
We recommend starting ART in HIV-positive patients who are commencing immunosuppressive
radiotherapy or chemotherapy for NADMs.
1B
1C
1C
1B
1D
GPP
2D
1B
GPP
GPP
GPP
2C
1A
1B
1C
1D
2C
1C
2.1.6.9 HIV-related cancers: what to start
8.3.3
We recommend that potential pharmacokinetic interactions between ARVs and systemic anticancer
therapy be checked before administration (with tools such as: http://www.hiv-druginteractions.
org).
We suggest avoiding ritonavir-boosted ART in HIV-positive patients who are to receive
cytotoxic chemotherapy agents that are metabolized by the cytochrome P450 (CYP450) enzyme
system.
We recommend against the use of ATV in HIV-positive patients who are to receive irinotecan.
We suggest avoiding ARV agents in HIV-positive patients who are to receive cytotoxic chemotherapy
agents that have overlapping toxicities.
GPP
2C
1C
2C
2.1.6.10 HIV-associated neurocognitive impairment: when to start
8.4.2
We recommend patients with symptomatic HIV-associated NC disorders start ART irrespective of CD4
lymphocyte count.
1C
2.1.6.11 HIV-associated neurocognitive impairment: what to start
8.4.3
We recommend patients with HIV-associated NC disorders start standard combination ART
regimens.
1C
2.1.6.12 HIV-associated neurocognitive impairment: modification of antiretroviral therapy
8.4.4
In patients with ongoing or worsening NC impairment despite ART we recommend the following best
practice management:
• Reassessment for confounding conditions.
• Assessment of cerebrospinal fluid (CSF) HIV RNA, CSF HIV genotropism and genotyping of CSF HIV
RNA.
• In subjects with detectable CSF HIV RNA, modifications to ART should be based on plasma and CSF
genotypic and genotropism results.
2.1.6.13 Chronic kidney disease: when to start
8.5.1
We recommend patients with HIVAN start ART immediately irrespective of CD4 cell count.
We recommend patients with end-stage kidney disease who are suitable candidates for renal transplantation start ART irrespective of CD4 cell count.
2.1.6.14 Chronic kidney disease: what to start
8.5.2
We recommend against the use of ARV drugs that are potentially nephrotoxic, in patients with stages
3–5 chronic kidney disease (CKD) if acceptable alternative ARV agents are available.
We recommend dose adjustment of renally cleared ARV drugs in patients with reduced renal function.
GPP
1C
1C
GPP
GPP
2.1.6.15 Cardiovascular disease: what to start
8.6.4
We suggest avoiding: ABC, FPV/r and LPV/r in patients with a high cardiovascular disease (CVD) risk,
if acceptable alternative ARV drugs are available.
2C
2.1.6.16 Women: when to start
8.7.2
We recommend therapy-naïve HIV-positive women who are not pregnant start ART according to the
same indicators as in men (see Section 4: When to Start)
1A
2.1.6.17 Women: what to start
8.7.3
We recommend therapy-naïve HIV-positive women start ART containing two NRTIs and one of the
following: PI/r, NNRTI or INI, as per therapy-naïve HIV-positive men.
We recommend therapy-naïve HIV-positive women start ART with preferred or alternative NRTI
backbone and third agent as per therapy-naïve HIV-positive men (see Section 5.1: What to start:
summary recommendations).
Factors such as potential side effects, co-morbidities, drug interactions, patient preference and dosing
convenience need to be considered in selecting ART in individual women.
1A
1A
We recommend both HIV-positive women of childbearing potential and healthcare professionals who
prescribe ART are conversant with the benefits and risks of ARV agents for both the health of
HIV-positive women and for that of an unborn child.
We recommend that potential pharmacokinetic interactions between ARVs, hormonal contraceptive
agents and hormone replacement therapy be checked before administration (with tools such as:
http://www.hiv-druginteractions.org).
GPP
GPP
2.1.7 Reference
1 Brook G, Main J, Nelson M et al. BHIVA Viral Hepatitis Working Group. British HIV Association guidelines for the management of
coinfection with HIV-1 and hepatitis B or C virus 2010. HIV Med 2010; 11: 1–30.
2.2 Summary of auditable measures
Percentage of patients who confirm they have been given the opportunity to be involved in making decisions about their
treatment.
Proportion of patients with CD4 cell count <350 cells/mL not on ART.
Proportion of patients with CD4 cell count >350 cells/mL and an indication to start ART on ART.
Proportion of patients presenting with an AIDS-defining infection or with a serious bacterial infection and a CD4 cell count
<200 cells/mL started on ART within 2 weeks of initiation of specific antimicrobial chemotherapy.
Proportion of patients presenting with PHI and neurological involvement, or an AIDS-defining illness or confirmed CD4
cell count <350 cells/mL started on ART.
Record in patient’s notes of discussion, treatment with ART lowers risk of HIV transmission and an assessment of current
risk of transmission.
Proportion of therapy-naïve patients not starting ART containing two NRTIs and one of the following: PI/r, NNRTI or INI
(preferred or alternative agents).
Proportion of patients starting ART with TDF/FTC or ABC/3TC as the NRTI backbone.
Proportion of patients starting ART with ATV/r, DRV/r, EFV or RAL as the third agent.
Proportion of patients with undetectable VL <50 copies/mL at 6 and 12 months after starting ART.
Proportion of patients who switch therapy in the first 6 and 12 months.
Record in patient’s notes of HLA-B*57:01 status before starting ABC.
Record in patient’s notes of discussion and assessment of adherence and potential barriers to, before starting a new ART
regimen and while on ART.
Record in patient’s notes of provision or offer of adherence support.
Record in patient’s notes of potential adverse pharmacokinetic interactions between ARV drugs and other concomitant
medications.
Proportion of patients with undetectable VL on ART who, on stopping a regimen containing NNRTI in combination with
an NRTI backbone, are switched to PI/r for 4 weeks.
Number of patients with an undetectable VL on current regimen and documented previous NRTI resistance who have
switched a PI/r to either an NNRTI or INI as the third agent.
Number of patients on PI/r monotherapy as ART maintenance strategy in virologically suppressed patients and record of
rationale.
Record in patient’s notes of resistance result at ART initiation (if available) and at first VL >400 copies/mL and/or before
switch.
Record in patient’s notes of adherence assessment and tolerability/toxicity to ART, in patients experiencing virological
failure or repeated viral blips.
Number of patients experiencing virological failure on current ART regimen.
Proportion of patients experiencing virological failure switched to a new suppressive regimen within 6 months.
Proportion of patients on ART with previous documented HIV drug resistance with VL <50 copies/mL.
Record of patients with three-class virological failure with or without three-class resistance referred/discussed in multidisciplinary team with expert advice.
Proportion of patients with TB and CD4 cell count <100 cells/mL started on ART within 2 weeks of starting TB therapy.
Proportion of patients with active TB on anti-TB therapy started on ART containing EFV, TDF and FTC.
Proportion of patients with a CD4 cell count ⱖ500 cells/mL and an HBV DNA ⱖ2000 IU/mL and/or evidence of more than
minimal fibrosis commencing ART inclusive of anti-HBV antivirals.
Proportion of patients with a CD4 cell count <500 cells/mL receiving TDF/FTC or TDF/3TC as part of a fully suppressive
combination ART regimen.
Proportion of patients receiving 3TC or FTC as the sole active drug against HBV in ART.
Proportion of patients with a CD4 cell count <500 cells/mL commencing ART.
Among patients receiving DAAs for HCV genotype 1 with ART for wild type HIV, the percentage on a recommended
regimen, i.e. RAL with TDF plus FTC with boceprevir; or RAL or boosted ATV with standard dose telaprevir; or EFV with
increased dose 1125 mg tds telaprevir.
Proportion of patients with an AIDS-defining malignancy on ART.
Proportion of patients with a non-AIDS-defining malignancy on ART.
Record in patient’s notes of potential pharmacokinetic drug interactions between ARVs and systemic anticancer therapy.
Proportion of patients with symptomatic HIV-associated NC disorders on ART.
Proportion of patients with HIV-associated NC disorders on ART containing two NRTIs and one of the following: NNRTI,
or PI/r or INI.
Proportion of patients with HIVAN started on ART within 2 weeks of diagnosis of CKD.
Number of patients with CKD stages 3–5 on ARVs that are potentially nephrotoxic and record of rationale.
Record in patient’s notes of the calculated dose of renally cleared ARVs in patients with CKD stage 3 or greater.
Number of patients with high CVD risk on either ABC or FPV/r or LPV/r and record of rationale.
Proportion of HIV-positive women with CD4 cell count <350 cells/mL not on ART.
3.0 Patient involvement in decision-making
3.1 Recommendations
• We recommend patients are given the opportunity to be
involved in making decisions about their treatment
(GPP).
• Provision of treatment-support resources should include
in-house, independent and community information providers and peer-support resources.
3.1.1 Auditable measure
Percentage of patients who confirm they have been given
the opportunity to be involved in making decisions about
their treatment.
3.2 Rationale
Patients should be given the opportunity to be involved in
making decisions about their treatment [1]. Studies show
that trust, a good-quality relationship and good communication skills between doctor and patient are associated
with better adherence and treatment outcomes in HIV and
in other disease areas [2–6].
Studies have shown that patient beliefs about the necessity, efficacy and side effects of ART, the practicability of
taking it, and beliefs about their ability to adhere to
therapy, all affect adherence [7–9].
Before prescribing ART (treatment initiation or
switching), clinicians should assess:
• Patients’ readiness to take therapy.
• Their knowledge of its mode of action and efficacy, and
perceptions of their personal need for ART.
• Concerns about taking ART or specific ARV drugs,
including potential adverse effects.
• Concerns with possible adverse social consequences,
such as disclosure or interference with lifestyle.
• Their confidence that they will be able to adhere to the
medication (self-efficacy);
• Psychological or NC issues that could impact on
adherence;
• Socio-economic factors that could impact on adherence,
including, but not limited to, poverty, housing, immigration status or domestic violence.
Community advocacy and peer support are helpful in supporting a patient’s understanding and confidence around
treatments and help the patient’s readiness and decision to
start therapy. Community organizations in the UK have
been instrumental in providing a range of patientinformation resources and peer-support services, including
published and web-based information materials, telephone
advice lines, treatment advocates and peer-support groups,
working in collaboration with healthcare professionals.
They are an important and essential adjunct to clinic-based
services and are helpful in addressing the issues discussed
below.
A number of patient factors may affect adherence,
adverse effects and treatment outcomes. Depression is significantly associated with low adherence [10,11] and some
studies report an independent association between depression and mortality in people with HIV [12]. Adherence can
be improved by treating depression [13], so all patients
should be screened for depression before starting therapy,
using simple screening tools such as the Arroll twoquestion quick screen [14]. Patients should also be screened
for anxiety and for cognitive impairment.
Current problematic alcohol and recreational drug use
are also associated with low adherence [15–17], although a
history of injecting drug use, or even active use, is not
necessarily so [18]. Patients should be asked about alcohol
and recreational drug use and offered support to moderate
or manage it if desired.
Conversely, adherence has been associated with positive
experiences of quality of life such as having a meaningful
life, feeling comfortable and well cared for, using time
wisely, and taking time for important things [19]. Patient
self-management skills and courses that teach them have
been associated with both improved adherence and better
clinical outcomes in a number of studies [20–22] and it
may be helpful to patients to inform them of these and
other psychological support options locally available, in
line with the BPS/BHIVA Standards for Psychological
Support for Adults Living with HIV [23].
A patient’s socio-economic status has a more direct
effect on adherence and other healthcare behaviours, than
clinicians realize. For instance, a US study found that
poverty had a direct effect on adherence, largely due to
food insufficiency [24]. A 2010 report on poverty in people
with HIV in the UK found that 1-in-6 people with HIV was
living in extreme poverty, in many cases due to unsettled
immigration status [25]. Clinicians should be aware of
patients’ socio-economic status and refer to social support
where necessary.
Clinicians should establish what level of involvement
the patient would like and tailor their consultation style
appropriately. Clinicians should also consider how to
make information accessible and understandable to
patients (e.g. with pictures, symbols, large print and different languages) [1], including linguistic and cultural
issues. Youth is consistently associated with lower adherence to ART, loss to follow-up and other negative healthcare behaviours [26] and some studies have found an
independent association between poorer adherence and
attendance and female gender [27], so information and
consultation style should be age and gender appropriate
for the patient.
If there is a question about the patient’s capacity to make
an informed decision, this should be assessed using the
principles in the Mental Capacity Act 2005 [28].
Patients presenting at the clinic may be at different
stages of readiness to take therapy [29] and clinicians’ first
task is to assess their readiness, by means of open questions
rather than closed, before supporting and furthering
patients’ decisions on therapy. However, if a patient
presents in circumstances that necessitate starting ART
immediately, for example with certain AIDS diagnoses or
very low CD4 cell counts, then doctors should prescribe
ART and provide support for the patient’s adherence, especially through the first few weeks. Recognizing symptoms
that patients attribute to ART side effects might avoid loss
of adherence and deterioration of trust in the patient–
provider relationship [30,31].
A ‘perceptions and practicalities’ approach should be
used to tailor support to meet the needs of the individual,
to identify both the perceptual factors (such as beliefs
about ART) and practical factors (such as capacity and
resources) influencing adherence [8,32].
Supporting patients requires good communication not
just between clinician and patient but also between all
healthcare staff involved with their care, including those
in their HIV services, their GP and any clinicians
involved in management of co-morbid conditions.
Patients should be offered copies of letters about them
sent to their GP and other physicians. The advantages of
HIV status disclosure to the patient’s GP should be discussed and considered best practice, as several situations
require consensual clinical decision-making. A patient’s
decision not to disclose their status to their GP should,
however, always be respected, subject to the clinician’s
duty to protect vulnerable individuals.
Clinical Practice Guideline Number 76. 2009. Available at
http://guidance.nice.org.uk/CG76 (accessed April 2012).
2 Schneider J, Kaplan SH, Greenfield S, Li W, Wilson IB.
Better physician-patient relationships are associated with
higher reported adherence to antiretroviral therapy in
patients with HIV infection. J Gen Intern Med 2004; 19:
1096–1103.
3 Kremer H, Ironson G. To tell or not to tell: why people with
HIV share or don’t share with their physicians whether they
are taking their medications as prescribed. AIDS Care 2006;
18: 520–528.
4 Roberts KJ. Physician-patient relationships, patient
satisfaction, and antiretroviral medication adherence among
HIV-infected adults attending a public health clinic. AIDS
Patient Care STDS 2002; 16: 43–50.
5 Owens DM, Nelson DK, Talley NJ. The irritable bowel
syndrome: long-term prognosis and the physician–patient
interaction. Ann Intern Med 1995; 122:
107–112.
6 Vermeire E, Hearnshaw H, Van Royen P, Denekens J. Patient
adherence to treatment: three decades of research. A
comprehensive review. J Clin Pharm Ther 2001; 26:
331–342.
7 Horne R, Buick D, Fisher M et al. Doubts about necessity
and concerns about adverse effects: identifying the types of
beliefs that are associated with non-adherence to HAART.
Int J STD AIDS 2004; 15: 38–44.
8 Horne R, Cooper V, Gellaitry G, Date HL, Fisher M. Patients’
perceptions of highly active antiretroviral therapy in relation
to treatment uptake and adherence: the utility of the
necessity-concerns framework. J Acquir Immune Defic Syndr
2007; 45: 334–341.
9 Gonzalez JS, Penedo FJ, Llabre MM et al. Physical
symptoms, beliefs about medications, negative mood, and
10
11
12
3.3 References
1 National Collaborating Centre for Primary Care.
Medicines concordance and adherence: involving adults and
carers in decisions about prescribed medicines. National
13
long-term HIV medication adherence. Ann Behav Med 2007;
34: 46–55.
Gonzalez JS, Batchelder AW, Psaros C, Safren SA.
Depression and HIV treatment non-adherence: a review and
meta-analysis. J Acquir Immune Defic Syndr 2011; 58:
181–187.
Kacanek D, Jacobson DL, Spiegelman D et al. Incident
depression symptoms are associated with poorer HAART
adherence: a longitudinal analysis from the Nutrition for
Healthy Living study. J Acquir Immune Defic Syndr 2009;
53: 266–272.
Lima VD, Geller J, Bangsberg DR et al. The effect of
adherence on the association between depressive
symptoms and mortality among HIV-infected
individuals first initiating HAART. AIDS 2007; 21:
1175–1183.
Yun LW, Maravi M, Kobayashi JS et al. Antidepressant
treatment improves adherence to antiretroviral therapy
among depressed HIV-infected patients. J Acquir Immune
Defic Syndr 2005; 38: 432–438.
14 Arroll B, Khin N, Kerse N. Screening for depression in
primary care with two verbally asked questions: cross
sectional study. BMJ 2003; 327: 1144–1146.
15 Hendershot CS, Stoner SA, Pantalone DW, Simoni JM.
Alcohol use and antiretroviral adherence: review and
meta-analysis. J Acquir Immune Defic Syndr 2009; 52:
180–202.
16 Reback CJ, Larkins S, Shoptaw S. Methamphetamine abuse
as a barrier to HIV medication adherence among gay and
bisexual men. AIDS Care 2003; 15: 775–785.
17 Halkitis PN, Kutnick AH, Borkowski T, Parsons JT.
Adherence to HIV medications and club drug use among gay
and bisexual men. XIV International AIDS Conference.
MedFASH, 2011. Available at http://www.bhiva.org/
StandardsForPsychologicalSupport.aspx (accessed April
2012).
24 Kalichman SC, Grebler T. Stress and poverty predictors of
treatment adherence among people with low-literacy living
with HIV/AIDS. Psychosom Med 2010; 72: 810–816.
25 National AIDS Trust, Terrence Higgins Trust. Hardship Fund.
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27 Tapp C, Milloy MJ, Kerr T et al. Female gender predicts
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21 Gifford AL, Laurent DD, Gonzales VM, Chesney MA, Lorig
KR. Pilot randomized trial of education to improve
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4.0 When to start
4.1 Chronic infection
4.1.2 Rationale
To date there have been no published randomized trials
that directly assess whether treatment-naïve people with
higher CD4 cell counts should initiate ART immediately
rather than defer until the CD4 cell count falls to ⱕ350
cells/mL; while the START trial is addressing this question, results are not expected until 2016. Only one trial
[1] has randomized people with a CD4 cell count >350
cells/mL, but this used a comparator arm of delay of initiation of ARVs until the CD4 cell count has fallen below
250 cells/mL, and thus is likely to overestimate the apparent benefits of immediate treatment compared with starting at <350 cells/mL. There have been a number of
observational studies that have attempted to address this
issue [2–9], which have produced conflicting findings.
Some of these studies have failed to take into account the
lead time between an individual’s CD4 cell count falling
below the threshold for treatment and the date of starting
treatment [8]; as this may introduce serious bias into
treatment comparisons, these results do not resolve the
question whether it is better to start ART at higher CD4
cell counts.
Where studies have used methods that take lead time
into account, the statistical methods used are novel and
different approaches have been used. The analyses
reached substantially different conclusions on the mortality benefits of early ART initiation in people with a
CD4 cell count >350 cells/mL, and particularly in those
with CD4 cell count >500 cells/mL. Critically, none of
these methods is able fully to adjust for potential confounding, which might well be large in this scenario and
could create a bias that is in the same direction in all
studies. Thus, we do not believe that the evidence is currently sufficiently strong to recommend a change in
guidelines.
The current guidelines were produced via a rigorous
process following a thorough review of the medical literature. The recommendation in the 2012 guidelines on when
to start ART was that in chronic HIV infection, patients
should start ART if their CD4 count is below 350 cells/mL,
because the evidence suggests that the risk of disease
progression increases below this level – thus, in this group,
the benefits of ART clearly outweigh any possible disadvantages (i.e., side effects and the selection of drugresistant virus). Clinicians should not delay starting ART if
• We recommend patients with chronic infection start ART
if the CD4 cell count is ⱕ350 cells/mL (1A): it is important not to delay treatment initiation if the CD4 cell
count is close to this threshold.
The absolute risk of disease progression is significantly
higher for a given CD4 cell count in older people (see
Table 4.1), so consideration should be given to starting at
higher CD4 cell counts in older persons. Evidence from
cohort studies suggest that the risk of disease progression is
significantly higher once the CD4 cell count falls below
350 cells/mL. Therefore, it is important not to delay unnecessarily the initiation of ART if the CD4 cell count is close
to this threshold.
We recommend patients with the following conditions
start ART:
• AIDS diagnosis (e.g. KS) irrespective of CD4 cell count
(1A).
• HIV-related co-morbidity, including HIVAN (1C), idiopathic thrombocytopenic purpura (1C), symptomatic
HIV-associated NC disorders irrespective of CD4 cell
count (1C).
• Coinfection with HBV if the CD4 cell count is ⱕ500
cells/mL (1B) (see Section 8.2.2 Hepatitis B).
• Coinfection with HCV if the CD4 cell count is ⱕ500
cells/mL (1C) (Section 8.2.3 Hepatitis C).
• NADMs requiring immunosuppressive radiotherapy or
chemotherapy (1C) (Section 8.3.2 When to start ART:
non-AIDS-defining malignancies).
We suggest patients with the following conditions start
ART:
• Coinfection with HBV if the CD4 cell count is >500
cells/mL and treatment of hepatitis B is indicated (2B)
(see Section 8.2.2 Hepatitis B).
4.1.1.1 Auditable measures
Proportion of patients with CD4 cell count <350 cells/mL
not on ART.
Proportion of patients with CD4 cell count >350 cells/mL
and an indication to start ART not on ART.
Table 4.1 Predicted 6-month risk of AIDS in antiretroviral therapy-naive patients according to current age [(a) 25 years, (b) 35 years, (c) 45 years
and (d) 55 years], CD4 cell count, viral load and whether antiretroviral therapy is initiated immediately or deferred
Risk (%)
CD4 count (cells/mL)
Treatment
(a)
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
(b)
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
(c)
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
(d)
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Deferred
Initiated
Viral load
(copies/mL)
3000
10 000
30 000
100 000
300 000
3000
10 000
30 000
100 000
300 000
3000
10 000
30 000
100 000
300 000
3000
10 000
30 000
100 000
300 000
50
100
150
200
250
300
350
400
450
500
6.8
2.3
9.6
3.2
13.3
4.4
18.6
6.2
25.1
8.4
3.7
1.2
5.3
1.8
7.4
2.5
10.6
3.5
14.5
4.8
2.3
0.8
3.4
1.1
4.7
1.6
6.7
2.2
9.3
3.1
1.6
0.5
2.3
0.8
3.2
1.1
4.6
1.5
6.3
2.1
1.1
0.4
1.6
0.5
2.2
0.7
3.2
1.1
4.5
1.5
0.8
0.3
1.2
0.4
1.6
0.5
2.4
0.8
3.3
1.1
0.6
0.2
0.9
0.3
1.2
0.4
1.8
0.6
2.5
0.8
0.5
0.2
0.7
0.2
0.9
0.3
1.4
0.5
1.9
0.6
0.4
0.1
0.5
0.2
0.7
0.2
1.1
0.4
1.5
0.5
0.3
0.1
0.4
0.1
0.6
0.2
0.8
0.3
1.2
0.4
8.5
2.8
12.1
4.0
16.6
5.5
23.1
8.0
30.8
10.3
4.7
1.6
6.7
2.2
9.3
3.1
13.2
4.5
18.0
6.0
3.0
1.0
4.3
1.4
5.9
2.0
8.5
2.8
11.7
3.9
2.0
0.7
2.9
1.0
4.0
1.3
5.8
1.9
8.0
2.7
1.4
0.5
2.0
0.7
2.8
0.9
4.1
1.4
5.7
1.9
1.0
0.3
1.5
0.5
2.1
0.7
3.0
1.0
4.2
1.4
0.8
0.3
1.1
0.4
1.6
0.5
2.3
0.8
3.1
1.0
0.6
0.2
0.9
0.3
1.2
0.4
1.7
0.6
2.4
0.8
0.5
0.2
0.7
0.2
0.9
0.3
1.3
0.4
1.9
0.6
0.4
0.1
0.5
0.2
0.7
0.2
1.1
0.4
1.5
0.5
10.7
3.6
15.1
5.0
20.6
6.9
28.4
9.5
37.4
12.5
5.9
2.0
8.5
2.8
11.7
3.9
16.5
5.5
22.4
7.5
3.7
1.2
5.4
1.8
7.5
2.5
10.6
3.5
14.6
4.9
2.5
0.8
3.6
1.2
5.1
1.7
7.3
2.4
10.1
3.4
1.8
0.6
2.6
0.9
3.6
1.2
5.2
1.7
7.2
2.4
1.3
0.4
1.9
0.6
2.6
0.9
3.8
1.3
5.3
1.8
1.0
0.3
1.4
0.5
2.0
0.7
2.9
1.0
4.0
1.3
0.7
0.2
1.1
0.4
1.5
0.5
2.2
0.7
3.1
1.0
0.6
0.2
0.8
0.3
1.2
0.4
1.7
0.6
2.4
0.8
0.5
0.2
0.7
0.2
0.9
0.3
1.3
0.4
1.9
0.6
13.4
4.5
18.8
6.3
25.4
8.5
34.6
11.5
44.8
14.9
7.5
2.5
10.7
3.6
14.6
4.9
20.5
6.8
27.5
9.2
4.7
1.6
6.8
2.3
9.4
3.1
13.3
4.4
18.2
6.1
3.2
1.1
4.6
1.5
6.4
2.1
9.2
3.1
12.6
4.2
2.3
0.8
3.3
1.1
4.6
1.5
6.5
2.2
9.1
3.0
1.7
0.6
2.4
0.8
3.3
1.1
4.8
1.6
6.7
2.2
1.2
0.4
1.8
0.6
2.5
0.8
3.6
1.2
5.0
1.7
0.9
0.3
1.4
0.5
1.9
0.6
2.8
0.9
3.9
1.3
0.7
0.2
1.1
0.4
1.5
0.5
2.2
0.7
3.0
1.0
0.6
0.2
0.8
0.3
1.2
0.4
1.7
0.6
2.4
0.8
Predicted risk of AIDS if antiretroviral therapy (ART) is deferred is taken from [10]. The predicted 6-month risk if ART is initiated is based on the assumption
that the rate with immediate therapy initiation is one-third the rate without therapy initiation. This (probably conservative) value is based on considering
evidence from multiple sources, including references [11–16].
the CD4 count is close to (but above) 350 cells/mL. In
addition, some patients should start ART if their CD4 count
is above 350 cells/mL, including pregnant women, some
patients with hepatitis B and C, some patients with acute
HIV infection, patients needing immunosuppressive treatments for cancer, and also patients with some HIV-related
problems including symptomatic neurocognitive disorders,
severe thrombocytopenia and HIV-associated nephropathy.
Finally, patients wishing to start ART primarily to reduce
the risk of transmission to others should be allowed to do
so, at any CD4 cell count. This guidance has not changed
in this current revision.
The 2012 guidelines did not recommend that all patients
with CD4 counts below 500 cells/mL should start ART,
because there are no data from any randomised clinical
trial with a suitable comparator arm that provide
unequivocal evidence that individual benefits outweigh the
risks. Currently available data derive from cohort studies
which have been analysed in different ways, and which
cannot fully adjust for confounders, the effect of which
may be large. Specifically, the balance between any small
benefits of ART in this group and the risk of any side
effects is unclear. The current revision of the guidelines will
not alter this recommendation. The START trial (which is
continuing to recruit in many countries around the world)
is designed to specifically address exactly this issue for
people with CD4 counts > 500 cells/mL such that future
guidelines will have a sufficient evidence base to make an
informed decision when considering earlier initiation of
therapy for an individual patient.
The BHIVA treatment guidelines were developed primarily with patients from the UK in mind. In other settings,
where there are particularly high TB rates, constraints on
delivery of care, and high losses through the care and
treatment cascade, earlier ART initiation may be more
important to increase retention of patients in care after
diagnosis.
4.1.3 References
2011; 365: 493–505.
2 Braithwaite RS, Roberts MS, Chang CC et al. Influence of
alternative thresholds for initiating HIV treatment on
quality-adjusted life expectancy: a decision model. Ann
Intern Med 2008; 148: 178–185.
3 Braithwaite RS, Roberts MS, Goetz MB et al. Do benefits of
4
5
6
7
earlier antiretroviral treatment initiation outweigh harms for
individuals at risk for poor adherence? Clin Infect Dis 2009;
48: 822–826.
HIV-CAUSAL Collaboration, Cain LE, Logan R, Robins JM
et al. When to initiate combined antiretroviral therapy to
reduce mortality and aids-defining illness in HIV-infected
persons in developed countries. Ann Intern Med 2011; 154:
509–515.
When To Start Consortium, Sterne JA, May M, Costagliola D
et al. Timing of initiation of antiretroviral therapy in
AIDS-free HIV-1-infected patients: a collaborative analysis
of 18 HIV cohort studies. Lancet 2009; 373: 1352–1363.
Jaén A, Esteve A, Miró JM et al. Determinants of
HIV progression and assessment of the optimal time to
initiate highly active antiretroviral therapy: PISCIS Cohort
(Spain). J Acquir Immune Defic Syndr 2008; 47: 212–220.
Kitahata MM, Gange SJ, Abraham AG et al. Effect of early
versus deferred antiretroviral therapy for HIV on survival.
N Engl J Med 2009; 360: 1815–1826.
8 Plettenberg A, Brockmeyer NH, Haastert B et al. Impact of
earlier ART initiation on the immune status and clinical
course of treated patients on the basis of cohort data of the
German Competence Network for HIV/AIDS. Infection 2011;
39: 3–12.
9 Writing Committee for the CASCADE Collaboration. Timing
of HAART initiation and clinical outcomes in human
immunodeficiency virus type 1 seroconverters. Arch Intern
Med 2011; 171: 1560–1569.
10 Phillips A, Pezzotti P, CASCADE Collaboration. Short-term
risk of AIDS according to current CD4 cell count and viral
load in antiretroviral drug-naive individuals and those
treated in the monotherapy era. AIDS 2004; 18:
51–58.
11 Emery S, Neuhaus JA, Phillips AN et al. Major
clinical outcomes in antiretroviral therapy (ART)-naive
participants and in those not receiving ART at
baseline in the SMART Study. J Infect Dis 2008; 197:
1133–1144.
12 Katzenstein DA, Hammer SM, Hughes MD et al. The relation
of virologic and immunologic markers to clinical outcomes
after nucleoside therapy in HIV-infected adults with 200 to
500 CD4 cells per cubic millimeter. N Engl J Med 1996;
335: 1091–1098.
13 Marschner IC, Collier AC, Coombs RW et al. Use of changes
in plasma levels of human immunodeficiency virus type 1
RNA to assess the clinical benefit of antiretroviral therapy.
J Infect Dis 1998; 177: 40–47.
14 Hammer SM, Squires KE, Hughes MD et al. A controlled trial
of two nucleoside analogues plus indinavir in persons with
human immunodeficiency virus infection and CD4 cell
counts of 200 per cubic millimeter or less. N Engl J Med
1997; 337: 725–733.
15 Antiretroviral Therapy Cohort Collaboration. Importance of
baseline prognostic factors with increasing time since
initiation of highly active antiretroviral therapy:
collaboration analysis of cohorts of HIV-1-infected patients.
J Acquir Immune Defic 2007; 46: 607–615.
16 Sterne JA, Hernàn MA, Ledergerber B et al. Long-term
effectiveness of potent antiretroviral therapy in preventing
AIDS and death: a prospective cohort study. Lancet 2005;
366: 378–384.
4.2 Patients presenting with AIDS or a major infection
• We recommend patients presenting with an AIDSdefining infection, or with a serious bacterial infection
and a CD4 cell count <200 cells/mL, start ART within 2
weeks of initiation of specific antimicrobial chemotherapy (1B).
4.2.1.1 Auditable measure
Proportion of patients presenting with an AIDS-defining
infection or with a serious bacterial infection and a CD4
cell count <200 cells/mL started on ART within 2 weeks of
initiation of specific antimicrobial chemotherapy.
4.2.2 Rationale
This recommendation is largely based on the ACTG 5164
study that demonstrated fewer AIDS progressions/deaths
and improved cost-effectiveness when ART was commenced within 14 days (median 12 days; IQR 9–13 days)
compared with after completion of treatment for the acute
infection (median 45 days; IQR 41–55 days) [1,2]. Those
with TB as the primary infection were excluded from this
study, and the majority of patients enrolled had Pneumocystis pneumonia, followed by lower proportions with
cryptococcal meningitis and bacterial infections. The
patients were well enough to give informed consent and to
take oral medications, and therefore the findings may not
be generalizable to those who are severely unwell or
requiring intensive care. Previous observational data
suggest a survival benefit for HIV-positive patients who are
started on ART while in the intensive care unit [3,4], but
the data are insufficient to make a recommendation in this
group [3,4].
There was no increase in the incidence of immune reconstitution disorders (IRD) or adverse events generally with
early ART initiation in ACTG 5164 [1,5]. However, those
with intracranial opportunistic infections may be more
prone to severe IRDs with early ART initiation. Some data
suggest that caution should be particularly exercised with
cryptococcal meningitis: two studies from sub-Saharan
Africa have demonstrated an increased mortality with early
ART initiation; however, both were in very different
healthcare settings from the UK and one utilized antifungal
regimens that would not be preferred [6,7]. The COAT study
highlighted those with an acellular CSF and those with a
decreased Glasgow Coma Scale as being particularly prone
to increased mortality with early ART initiation [7].
Those presenting with TB and malignancies are discussed in Section 8.
4.2.3 References
1 Zolopa A, Andersen J, Powderly W et al. Early antiretroviral
therapy reduces AIDS progression/death in individuals with
acute opportunistic infections: a multicenter randomized
strategy trial. PLoS ONE 2009; 4: e5575.
2 Sax PE, Sloan CE, Schackman BR et al. Early antiretroviral
therapy for patients with acute aids-related opportunistic
infections: a cost-effectiveness analysis of ACTG A5164. HIV
Clin Trials 2010; 11: 248–259.
3 Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved
survival with highly active antiretroviral therapy in
HIV-infected patients with severe Pneumocystis carinii
pneumonia. AIDS 2003; 17: 73–80.
4 Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit
of antiretroviral therapy on survival of human
immunodeficiency virus-infected patients admitted to an
intensive care unit. Crit Care Med 2009; 37: 1605–1611.
5 Grant PM, Komarow L, Andersen J et al. Risk factor analyses
for immune reconstitution inflammatory syndrome in a
randomized study of early vs. deferred ART during an
opportunistic infection. PLoS ONE 2010; 5: e11416.
6 Makadzange AT, Ndhlovu CE, Takarinda K et al. Early versus
delayed initiation of antiretroviral therapy for concurrent HIV
infection and cryptococcal meningitis in sub-Saharan Africa.
Clin Infect Dis 2010; 50: 1532–1538.
7 Boulware D, Meya D, Muzoora C et al. ART initiation within
the first 2 weeks of cryptococcal meningitis is associated with
higher mortality: a multisite randomized trial. 20th Conference
on Retroviruses and Opportunistic Infections. Atlanta, GA.
March 2013. [Abstract OA144].
4.3 Treatment of primary HIV infection
We recommend patients presenting with PHI and meeting
any one of the following criteria start ART:
• Neurological involvement (1D).
• Any AIDS-defining illness (1A).
• Confirmed CD4 cell count <350 cells/mL (1C).
Proportion of patients presenting with PHI and neurological involvement, or an AIDS-defining illness or confirmed
CD4 cell count <350 cells/mL started on ART.
4.3.2 Rationale
The scientific rationale for treating with ART in PHI is as
follows.
(i) Preservation of specific anti-HIV CD4 T lymphocytes
that would otherwise be destroyed by uncontrolled
viral replication, the presence of which is associated
with survival in untreated individuals [1].
(ii) Reduction in morbidity associated with high viraemia
and profound CD4 cell depletion during acute infection [2–4].
(iii) Reduction in the enhanced risk of onward transmission of HIV associated with PHI [5–10].
Treatment of patients with PHI who present with AIDSdefining illnesses, neurological disease or a CD4 cell count
of <350 cells/mL is consistent with the recommendations
for patients with chronic infection. The rationale for treating patients with neurological disease is that ART may lead
to regression of otherwise irreversible neurological disease
(although there is no high-quality evidence for this effect
of treatment in primary infection). Data from the CASCADE
collaboration [11] showed that patients with primary infection, who had at least one CD4 cell count of <350 cells/mL
in the first 6 months of infection, had a significantly
greater mortality than those whose CD4 cell counts
remained above this threshold, which supports early treatment in patients with lower CD4 cell counts.
Multiple observational studies have shown encouraging
but inconclusive results following short-course ART initiated in PHI for individuals in whom ART would not otherwise be indicated [12,13]. There have been three RCTs
comparing the role of interrupted ART initiated in PHI on
time to reach CD4 <350 cells/mL or the need for initiation
of lifelong ART [14–16]. Overall there was a modest benefit
in terms of delaying the decline in CD4 cell count, or time
from seroconversion, to requiring initiation of lifelong ART
following a 48- [16] or 60- [15] week course of ART. A post
hoc analysis from the SPARTAC trial [16] showed a nonsignificant trend towards benefit in time to CD4 cell count
<350 cells/mL when ART was initiated closer to the time of
infection (HR 0.48; P = 0.09). This randomized study supported cohort studies in which a more rapid rate of CD4 cell
loss was seen in individuals presenting within 12 weeks of
a negative HIV antibody test [17,18].
For this reason, we suggest that the following are discussed with those presenting with a very short test interval
(ⱕ12 weeks), in particular, those with severe symptoms of
seroconversion such as rash, fever, weight loss, persistent
lymphadenopathy, diarrhoea >4 days, malaise, headaches
or laboratory evidence of acute HIV infection (e.g. as
defined in SPARTAC [16]).
• A 48-week course of ART showed a benefit in surrogate
markers of HIV-disease progression: delaying CD4
decline and lowering viral set point up to 60 weeks after
stopping therapy. There was no such benefit from 12
weeks of ART. In those individuals presenting within 12
weeks of infection, this effect was more marked;
however, there is no clear evidence of long-term clinical
benefit of ART in this setting.
• No study has examined whether ART started during, or
soon after, PHI should be continued long term, but most
clinicians would recommend that irrespective of indication to start ART, once initiated, it should be continued
indefinitely. Discontinuation of ART in the context of
treatment of PHI was not commonly associated with
morbidity, however [15,16].
• Initiation of a PI-based regimen is recommended if
therapy is started before the availability of a genotype
result, based on the prevalence of transmitted rates of
drug resistance in the UK [19].
• There is no specific evidence to support the role of ART
in PHI to prevent onward transmission of virus but there
is little reason to consider that ART is any less effective
in reducing infectivity at this time, so long as viral
suppression has been achieved [20].
• Patients with recently diagnosed PHI may be in a particularly vulnerable psychological state, and thus illprepared to commit to starting long-term treatment.
4.3.3 References
1 Rosenberg ES, Altfeld M, Poon SH et al. Immune control of
HIV-1 after early treatment of acute infection. Nature 2000;
407: 523–526.
2 Socías ME, Sued O, Laufer N et al.; Grupo Argentino de
Seroconversión Study Group. Acute retroviral syndrome and
high baseline viral load are predictors of rapid HIV
progression among untreated Argentinean seroconverters.
J Int AIDS Soc 2011; 14: 40.
3 Lodi S, Phillips A, Touloumi G et al.; CASCADE
Collaboration in EuroCoord. Time from human
immunodeficiency virus seroconversion to reaching CD4+
cell count thresholds <200, <350, and <500 cells/mm3:
assessment of need following changes in treatment
guidelines. Clin Infect Dis 2011; 53: 817–825.
4 Goujard C, Bonarek M, Meyer L et al.; Agence Nationale de
Recherche sur le Sida PRIMO Study Group. CD4 cell count
and HIV DNA level are independent predictors of disease
progression after primary HIV type 1 infection in untreated
patients. Clin Infect Dis 2006; 42: 709–715.
5 Powers KA, Ghani AC, Miller WC et al. The role of acute and
early HIV infection in the spread of HIV and implications
for transmission prevention strategies in Lilongwe, Malawi:
a modelling study. Lancet 2011; 378: 256–268.
6 Miller WC, Rosenberg NE, Rutstein SE, Powers KA. Role of
acute and early HIV infection in the sexual transmission of
HIV. Curr Opin HIV AIDS 2010; 5: 277–282.
7 Pinkerton SD. Probability of HIV transmission during acute
infection in Rakai, Uganda. AIDS Behav 2008; 12:
677–684.
8 Hollingsworth TD, Anderson RM, Fraser C. HIV-1
transmission, by stage of infection. J Infect Dis 2008; 198:
687–693.
9 Pao D, Fisher M, Hué S et al. Transmission of HIV-1 during
primary infection: relationship to sexual risk and sexually
transmitted infections. AIDS 2005; 19: 85–90.
10 Sabin C, Pillay D. Determinants of HIV-1 transmission in
men who have sex with men: a combined clinical,
epidemiological and phylogenetic approach. AIDS 2010; 24:
1739–1747.
11 Lodi S, Fisher M, Phillips A et al.; CASCADE Collaboration.
Identification of severe primary HIV infection through
clinical, immunological and virological definitions. 19th
Conference on Retroviruses and Opportunistic Infections.
Seattle, WA. February 2012 [Abstract 550].
12 Bell SK, Little SJ, Rosenberg ES. Clinical management of
acute HIV infection: best practice remains unknown. J Infect
Dis 2010; 202 (Suppl 2): S278–S288.
13 Fidler S, Fox J, Porter K, Weber J. Primary HIV infection: to
treat or not to treat? Curr Opin Infect Dis 2008; 21: 4–10.
14 Hogan C, DeGruttola V, Sun X et al. The SETPOINT study
(ACTG A5127): effect of immediate versus deferred
antiretroviral therapy on virologic set point in recently
HIV-1-infected individuals. J Infect Dis 2012; 205: 87–96.
15 Grijsen ML, Steingrover R, Wit FW et al. No treatment
versus 24 or 60 weeks of antiretroviral treatment during
primary HIV infection: The randomised Primo SHM trial.
PLoS Med 2012; 9: e1001196.
16 SPARTAC, Fidler S, on behalf of the SPARTAC trial
investigators. The effect of a short course of ART in primary
HIV infection. Final results from an international
randomised controlled study. 6th IAS on HIV Pathogenesis,
Treatment and Prevention. Rome, Italy. July 2011 [Abstract
WELBX06].
17 The CASCADE Collaboration. The relationships between the
HIV test interval, demographic factors and HIV disease
progression. Epidemiol Infect 2001; 127: 91–100.
18 Tyrer F, Walker AS, Gillett J, Porter K, UK Register of HIV
Seroconverters. The relationship between HIV seroconversion
illness, HIV test interval and time to AIDS in a seroconverter
cohort. Epidemiol Infect 2003; 131: 1117–1123.
19 Cane P, Chrystie I, Dunn D et al.; UK Group on Transmitted
HIV Drug Resistance. Time trends in primary resistance to
HIV drugs in the United Kingdom: multicentre observational
study. BMJ 2005; 331: 1368.
2011; 365: 493–505.
reduce the risk of transmission to partners, this decision
is respected and ART is started (GPP).
4.4.1.1 Auditable measures
Record in patient’s notes of discussion that treatment with
ART lowers risk of HIV transmission and an assessment of
current risk of transmission.
The discussion should include the following:
• The decision to start ART is the patient’s choice and must
not be due to pressure from partners or others.
• ART lowers, rather than eliminates, the risk of transmission; other prevention strategies, including male and
female condoms continue to be recommended to address
concerns of any residual risk of transmission.
• For a patient with a CD4 cell count >350 cells/mL, it is
uncertain whether any benefits of immediate treatment
to their own health will be outweighed by any harm.
• Condoms, both male and female, continue to be recommended as protection from other sexually transmitted
infections and unplanned pregnancy.
• There are risks associated with interrupting ART,
and once started, it should generally be continued
indefinitely.
• The evidence that ART lowers the risk of transmission
mainly relates to vaginal sex. Although ART is highly
likely to reduce the risk of transmission for anal sex, the
residual risk could be higher than that seen in studies for
vaginal sex. There are currently few data to inform this.
• High and consistent adherence to ART is required to maintain viral suppression and minimize transmission risk.
• Taking ART does not result in immediate complete viral
suppression; it usually takes several months to achieve an
undetectable VL in blood.
• The use of ART to reduce transmission risk is a particularly important consideration in serodiscordant
heterosexual couples wishing to conceive and it is recommended that the HIV-positive partner be on fully
suppressive ART.
4.4.2 Rationale
4.4 Treatment to reduce transmission
• We recommend the evidence that treatment with ART
lowers the risk of transmission is discussed with all
patients, and an assessment of the current risk of transmission to others is made at the time of this discussion
(GPP).
• We recommend following discussion, if a patient with a
CD4 cell count >350 cells/mL wishes to start ART to
The potential effect of HIV treatment to reduce the risk of
onward sexual transmission should be discussed with all
patients as a part of safer sex messages in general. The
discussion should include the HIV status of their partner(s)
and whether ART is indicated for their own health.
This discussion should make clear that there is good
evidence from one RCT (HPTN 052) [1] that ART treatment
can markedly reduce (by 96%) the risk of transmission to
HIV-negative partners. This is supported by the secondary
outcomes of another trial [2] that also found a marked
reduction in transmission from partners taking ART (by
92%). It is important to note that only 3% of the couples in
HPTN 052 were men who have sex with men and the
Partners in Prevention study was conducted entirely in
heterosexual couples. The evidence base thus relates mainly
to the risk of transmission for vaginal sex in heterosexual
couples. It seems likely that a reduction in risk will also be
seen for anal sex, but this is the subject of ongoing studies.
Before these randomized controlled studies, the evidence
base for treatment to reduce transmission was based on a
number of cohort studies that found that transmission
between heterosexual couples where the HIV-positive
partner had an undetectable VL on treatment was very rare
or did not occur [3–7].
Viral suppression due to ART is usually as effective in
reducing VL in semen [8] and in the rectum [9] as in plasma.
This suggests that in the absence of other facilitators of
transmission such as sexually transmitted infections, ART
would be expected to be as effective in reducing infectiousness in men who have sex with men and other populations
as it is in heterosexuals. Indirect evidence comes from a
study of men who have sex with men attending HIV
treatment services where ART was associated with a 96%
reduction in HIV transmission [10].
Condoms should still be recommended to protect from
other sexually transmitted infections, and to lower further
any residual risk of transmission.
Patients should be informed that taking ART does not
result in immediate viral suppression. Studies have shown
that the mean time to suppression of VL to <50 copies/mL
in patients taking ART is about 90 days, and that a proportion may take 9 months or more [11]. Patients should
also be informed about the possibility of virological failure
leading to transmission of HIV. Decisions on condom use
and safer sex should always be based on a recent VL test
result and not on an assumption that taking ART implies
non-infectiousness.
For serodiscordant heterosexual couples wishing to conceive, irrespective of the method used for conception, the
HIV-positive partner will need to be on ART with an
undetectable plasma VL, regardless of his/her CD4 cell count
or clinical status. This is likely to reduce the risk of transmission sufficiently to be the only risk-reduction method
some couples will want, but additional measures such as
sperm washing, artificial insemination and potentially preexposure prophylaxis (PrEP) to the HIV-negative partner
have either been recommended in previous guidance [12] or
are currently being assessed for couples wishing to address
concerns of any residual risk of transmission.
Details of the use of ART to prevent mother-to-child
transmission are covered in the BHIVA guidelines for the
management of HIV infection in pregnant women 2012 [13].
4.4.3 References
2011; 365: 493–505.
2 Donnell D, Baeten JM, Kiarie J et al. Heterosexual HIV-1
transmission after initiation of antiretroviral therapy: a
prospective cohort analysis. Lancet 2010; 375: 2092–2098.
3 Castilla J, del Romero J, Hernando V et al. Effectiveness of
highly active antiretroviral therapy in reducing heterosexual
transmission of HIV. J Acquir Immune Defic Syndr 2005;
40: 96–101.
4 Del Romero J, Castilla J, Hernando V, Rodriguez C, Garcia S.
Combined antiretroviral treatment and heterosexual
transmission of HIV-1: cross sectional and prospective
cohort study. BMJ 2010; 340: c2205.
5 Melo M, Varella I, Nielsen K, Turella L, Santos B.
Demographic characteristics, sexual transmission and CD4
progression among heterosexual HIV-serodiscordant couples
followed in Porto Alegre, Brazil. 16th International AIDS
Conference. Toronto. August 2006 [Abstract TUPE0430].
6 Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual
transmission of HIV according to viral load and
antiretroviral therapy: systematic review and meta-analysis.
AIDS 2009; 23: 1397–1404.
7 Barreiro P, del Romero J, Leal M et al. Natural pregnancies
in HIV-serodiscordant couples receiving successful
antiretroviral therapy. J Acquir Immune Defic Syndr 2006;
43: 324–326.
8 Kalichman SC, Di Berto G, Eaton L. Human
immunodeficiency virus viral load in blood plasma and
semen: review and implications of empirical findings. Sex
Transm Dis 2008; 35: 55–60.
9 Kelley CF, Haaland RE, Patel P et al. HIV-1 RNA rectal
10
11
12
13
shedding is reduced in men with low plasma HIV-1 RNA
viral loads and is not enhanced by sexually transmitted
infections in the rectum. J Infect Dis 2011; 204: 761–767.
Fisher M, Pao D, Brown AE et al. Determinants of HIV-1
transmission in men who have sex with men: a combined
clinical, epidemiological and a phylogenetic approach. AIDS
2010; 24: 1739–1747.
Perez-Hoyos S, Rodríguez-Arenas MA, García de la Hera M
et al. Progression to AIDS and death and response to HAART
in men and women from a multicentre hospital-based
cohort. J Womens Health 2007; 16: 1052–1061.
Fakoya A, Lamba H, Mackie N et al. BHIVA, BASHH and
FSRH guidelines for the management of sexual and
reproductive health of people living with HIV infection
2008. HIV Med 2008; 9: 681–720.
Taylor GP, Clayden P, Dhar J et al. BHIVA guidelines for the
Med 2012; 13 (Suppl. 2): 87–157.
5.0 What to start
5.1 Summary recommendations
• We recommend therapy-naïve patients start ART containing two NRTIs plus one of the following: PI/r, NNRTI
or INI (1A).
Summary recommendations for choice of ART:
NRTI backbone
Third agent
Preferred
Alternative
TDF and FTC
ATV/r
DRV/r
EFV
RAL
ELV/COBI
RPV‡
ABC and 3TC*‡
LPV/r
FPV/r
NVP†
*ABC is contraindicated if patient is HLA-B*57:01 positive.
†NVP is contraindicated if baseline CD4 cell count is >250/400 cells/mL in
women/men.
‡Use recommended only if baseline VL is <100 000 copies/mL: RPV as a
third agent; abacavir and 3TC as the NRTI backbone.
The presence or future risk of co-morbidities and potential
adverse effects need to be considered in the choice of ARV
drugs in individual patients.
Proportion of therapy-naïve patients not starting ART containing two NRTIs and one of the following: a PI/r, or an
NNRTI or an INI (preferred or alternative agents).
Proportion of patients starting ART with either TDF/FTC
or ABC/3TC as the NRTI backbone.
Proportion of patients starting ART with ATV/r, or
DRV/r, or EFV or RAL as the third agent.
Proportion of patients with undetectable VL <50
copies/mL at 6 months and at 12 months after starting
ART.
Proportion of patients who switch therapy in the first 6
and 12 months.
Record in patient’s notes of HLA-B*57:01 status before
starting ABC.
5.2 Introduction
For the ‘which NRTI backbone’ and ‘which third agent’
questions, evidence profiles and summary of findings
tables were constructed to assess quality of evidence across
predefined treatment outcomes (Appendices 3 and 4). Evidence from RCTs and systematic reviews was identified
from a systematic literature review (Appendix 2). Outcomes
were scored and ranked (critical, important, not important)
by members of the Writing Group. The following were
ranked as critical outcomes: viral suppression at 48/96
weeks, protocol-defined virological failure, drug resistance,
quality of life, discontinuation for adverse events and
grade 3/4 adverse events (overall), rash and alanine
transaminase/aspartate transaminase elevation.
Treatments were compared and differences in critical
outcomes assessed. Where there were differences, consensus opinion was sought to determine whether the difference in size of effect was above the threshold for clinical
decision-making. If conflicting differences were detected,
the balance of outcomes was based on consensus opinion
of the Writing Group.
A treatment was defined as preferred or alternative to
indicate strong or conditional recommendations and the
decision based on the assessment of critical outcomes and
the balance of desirable and undesirable effects in a general
ART-naïve patient population. ‘Preferred’ indicates a strong
recommendation that most clinicians and patients would
want to follow unless there is a clear rationale not to do so.
‘Alternative’ indicates a conditional recommendation and is
an acceptable treatment option for some patients and might
be, in selected patients, the preferred option.
Factors including potential side effects, co-morbidities,
patient preference and drug interactions need to be taken
into account when selecting an ART regimen in individual
patients, and may include both preferred and alternative
treatment options.
For guidance on assessment of patients before initiation
of ART and monitoring of patients on ART the reader
should consult the BHIVA guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals
2011 [1].
5.3 Which nucleoside reverse transcriptase inhibitor
backbone
• We recommend therapy-naïve patients start combination ART containing TDF and FTC as the NRTI backbone
(1A).
• We suggest ABC and 3TC is an acceptable alternative
NRTI backbone in therapy-naïve patients who, before
starting ART, have a baseline VLⱕ100 000 copies/mL
(2A).
• ABC must not be used in patients who are HLA-B*57:01
positive (1A).
5.3.2 Rationale
Three RCTs have compared TDF-FTC with ABC-3TC as the
NRTI backbone in combination with different third agents:
ATV/r or EFV [2–6], EFV [7–9] and LPV/r [10].
Assessment of virological efficacy as a critical outcome
was complicated by different definitions across the three
studies. In our analysis for GRADE (see Appendix 3.1),
there was no difference in rates of virological suppression
at 48 weeks or 96 weeks but the analysis excluded the
largest of the three trials (ACTG 5202) and the quality of
evidence for this outcome was assessed as low or very low.
Assessment of the risk of protocol-defined virological
failure at 48 weeks favoured TDF-FTC (RR 0.76, 95% CI
0.53–1.07), although the effect was not statistically significant and heterogeneity in the analysis was relatively high
(I2 46%). Assessment of protocol-defined virological failure
at 96 weeks showed a significant difference favouring
TDF-FTC (RR 0.73, 95% CI 0.59–0.92). Data were only
available from one study [4] for this analysis; however, this
was by far the largest of the three trials and the quality of
evidence assessment for this outcome was rated as high.
The difference in virological failure was assessed by the
Writing Group to be large enough to be above the clinical
threshold for decision-making. The difference equates to a
number needed to treat to prevent one case of virological
failure of approximately 20 patients treated for 1 year.
The results of ACTG 5202 [2–4] are complicated by early
termination of those individuals with a baseline VL
>100 000 copies/mL at the recommendation of the data and
safety monitoring board due to significantly inferior performance in those subjects receiving ABC-3TC. No difference in virological efficacy between the TDF-FTC and
ABC-3TC arms was seen in those in the lower VL stratum
(baseline VL <100 000 copies/mL). The subsequent 96-week
analysis, after discontinuation of those subjects in the
higher VL stratum, may therefore underestimate the difference between the two backbones. HLA-B*57:01 screening
was not routine in ACTG 5202 and this potentially may
have influenced some of the safety endpoints, but appears
not to have influenced the primary virological outcome. In
the higher VL strata the number of patients with suspected
hypersensitivity reactions was equal between both arms
and virological failure in these patients was infrequent.
With regard to the assessment of the other critical and
important outcomes, including drug resistance, discontinuation for adverse events and lipodystrophy, no difference
was shown between TDF-FTC and ABC-3TC. No data were
available to assess quality of life outcomes. For grade 3/4,
adverse events (all) and grade 3/4 alanine transaminase/
aspartate transaminase elevation there were trends that
favoured TDF-FTC (see Appendix 3.1).
Although the rate of drug resistance was not different
between the NRTI backbones, the number developing drug
resistance was higher numerically in those receiving ABC3TC, given the higher rate of virological failure.
The only outcome that significantly favoured ABC-3TC
was bone mineral density but no difference in bone fractures was identified.
It is the view of the Writing Group that, given the
favourable virological outcomes of TDF-FTC compared
with ABC-3TC and the lack of other significant differences
in critical and important adverse event outcomes, TDF-FTC
is recommended as the preferred NRTI backbone of choice.
ABC-3TC is an acceptable alternative option in patients
with a baseline VL <100 000 copies/mL, but must only be
used after ensuring a patient is HLA-B*57:01 negative.
When selecting an NRTI backbone, factors such as
potential side effects, co-morbidities, patient preference
and cost should also be considered. Observational studies
have variably reported associations between ABC and CVD
[11–13], and TDF may cause renal disease [14]. These
aspects will be discussed in more detail in Section 8.
However, based on the balance of current evidence we
suggest ABC is not used in individuals at high risk of CVD
(see Section 8.6 Cardiovascular disease) and TDF is not
used in patients with stage 3–5 CKD or at high risk of
progression of CKD (see Section 8.5 Chronic kidney
disease) if acceptable alternative ARVs are available.
The Writing Group believes there is no routine role for
other NRTI backbones in the treatment of ART-naïve
patients. Zidovudine (ZDV)-3TC may be considered in
certain specific circumstances (e.g. pregnancy; see BHIVA
Guidelines for the Management of HIV Infection in Pregnant Women 2012 [15]) but should not be given routinely
due to the proven association with mitochondrial toxicity,
particularly lipoatrophy, with ZDV. There is no place for the
use of stavudine- or didanosine-containing regimens as
initial therapy, due to the associations with significant
mitochondrial and hepatic toxicities.
5.3.4 References
1 Asboe D, Aitken C, Boffito M et al. BHIVA guidelines for the
routine investigation and monitoring of adult HIV-1-infected
individuals 2011. HIV Med 2012; 13: 1–44. Available at
http://www.bhiva.org/PublishedandApproved.aspx (accessed
April 2012).
2 Sax PE, Tierney C, Collier AC et al. Abacavir–lamivudine
versus tenofovir–emtricitabine for initial HIV-1 therapy. N
Engl J Med 2009; 361: 2230–2240.
3 Sax PE, Tierney C, Collier AC et al. Abacavir/lamivudine
versus tenofovir DF/emtricitabine as part of combination
regimens for initial treatment of HIV: final results. J Infect
Dis 2011; 204: 1191–1201.
4 Daar ES, Tierney C, Fischl MA et al. Atazanavir plus
ritonavir or efavirenz as part of a 3-drug regimen for
initial treatment of HIV-1. Ann Intern Med 2011; 154:
14 Mocroft A, Kirk O, Reiss P et al. Estimated glomerular
filtration rate, chronic kidney disease and antiretroviral
drug use in HIV-positive patients. AIDS 2010; 24:
1667–1678.
15 Taylor GP, Clayden P, Dhar J et al. BHIVA guidelines for the
management of HIV infection in pregnant women 2012.
HIV Med 2012; 13 (Suppl. 2): 87–157.
445–456.
5 McComsey GA, Kitch D, Daar ES et al. Bone mineral density
and fractures in antiretroviral-naive persons randomized to
receive abacavir-lamivudine or tenofovir disoproxil
fumarate-emtricitabine along with efavirenz or atazanavirritonavir: AIDS Clinical Trials Group A5224s, a Substudy of
ACTG A5202. J Infect Dis 2011; 203: 1791–1801.
6 McComsey GA, Kitch D, Sax PE et al. Peripheral and central
fat changes in subjects randomized to abacavir-lamivudine
or tenofovir-emtricitabine with atazanavir-ritonavir or
efavirenz: ACTG Study A5224s. Clin Infect Dis 2011; 53:
185–196.
7 Post FA, Moyle GJ, Stellbrink HJ, Domingo P, Podzamczer
D. Randomized comparison of renal effects, efficacy, and
safety with once-daily abacavir/lamivudine versus
tenofovir/emtricitabine, administered with efavirenz, in
antiretroviral-naive, HIV-1-infected adults: 48-week results
from the ASSERT Study. J Acquir Immune Defic Syndr 2010;
55: 49–57.
8 Stellbrink HJ, Orkin C, Arribas JR et al. Comparison of
changes in bone density and turnover with
abacavir-lamivudine versus tenofovir-emtricitabine in
HIV-infected adults: 48-week results from the ASSERT
Study. Clin Infect Dis 2010; 51: 963–972.
9 Moyle GJ, Stellbrink HJ, Compston J et al. Comparison of
bone and renal toxicities in the ASSERT study: final 96
week results from a prospective randomized safety trial.
Antivir Ther 2010; 15 (Suppl 4): A19.
10 Smith KY, Patel P, Fine D et al. Randomized, double-blind,
placebo-matched, multicenter trial of abacavir/lamivudine or
tenofovir/emtricitabine with lopinavir/ritonavir for initial
HIV treatment. AIDS 2009; 23: 1547–1556.
11 Obel N, Farkas DK, Kronborg G et al. Abacavir and risk of
myocardial infarction in HIV-infected patients on highly
active antiretroviral therapy: a population-based nationwide
cohort study. HIV Med 2010; 11: 130–136.
12 Worm SW, Sabin C, Weber R et al. Risk of myocardial
infarction in patients with HIV infection exposed to specific
individual antiretroviral drugs from the 3 major drug
classes: the data collection on adverse events of anti-HIV
drugs (D:A:D) study. J Infect Dis 2010; 201: 318–330.
13 Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P.
Abacavir use and risk of acute myocardial infarction and
cerebrovascular events in the HAART era. Clin Infect Dis
2011; 53: 84–91.
5.4 Which third agent
• We recommend therapy-naïve patients start combination ART containing ATV/r, DRV/r, EFV, RAL or ELV/
COBI as the third agent (1A).
• We suggest that for therapy-naïve patients LPV/r and
FPV/r are acceptable alternative PIs, and NVP and RPV
are acceptable alternative NNRTIs (2A).
• NVP must only be used according to CD4 criteria and
RPV should only be used in patients with baseline
VL <100 000 copies/mL.
5.4.2 Rationale
The BHIVA Guidelines for the Treatment of HIV-1-infected
Adults with Antiretroviral Therapy 2008 [1] recommended
EFV as the preferred third agent in view of significantly
better virological outcomes compared with LPV/r [2]. A
similar outcome was subsequently reported in a smaller
randomized study of patients commencing ART with
advanced disease, as defined by a CD4 cell count of <200
cells/mL [3].
Since the 2008 guidelines, a number of comparative
studies against either EFV, LPV/r or ATV/r have been
reported, investigating alternative third agents.
• Comparison with EFV: ATV/r [4–10]; RAL [11–14]; RPV
[15–17]; ELV/COBI [18].
• Comparison with LPV/r: ATV/r [17]; DRV/r [20–22].
• Comparison with r/ATV; ELV/COBI [19].
For the current guidelines, evidence for agreed treatment
outcomes for each potential third agent was compared with
EFV, either directly or indirectly depending on the available
evidence (Appendix 3).
ATV/r and RAL have been compared directly with EFV in
RCTs. For critical virological efficacy and safety outcomes,
no differences were identified between EFV and either
ATV/r or RAL. For these outcomes the quality of evidence
was rated as high or moderate.
There was a difference in the rate of drug resistance
favouring ATV/r (RR 3.94, 95% CI 2.37–6.56; P < 0.00001)
but the overall rate of emergent drug resistance was low for
both treatments. This difference is a class effect and has
previously been reported for other NNRTIs and PI/r.
Differences were also identified in the rate of grade 3/4
central nervous system (CNS) events and the rate of lipid
abnormalities favouring both ATV/r and RAL. These differences may well influence the choice between preferred
third agents for individual patients.
There are no RCTs comparing DRV/r vs. EFV directly.
Thus an indirect comparison was undertaken using data
from studies comparing DVR/r vs. LPV/r [20–22] and
LPV/r vs. EFV [2,3] to assess outcomes between the two
treatment options. Some differences between these studies
were identified in terms of comparability and are outlined
in Appendix 3. Overall, these differences were judged
insufficient to invalidate an indirect comparison between
EFV and DRV/r.
Comparing DRV/r and LPV/r there were clinically significant differences in the critical outcomes virological
suppression, discontinuation due to adverse events and
serious adverse events in favour of DRV/r but no differences in the critical outcomes virological failure and drug
resistance. Comparing EFV and LPV/r there were clinically
significant differences in the critical outcomes virological
failure and suppression at 96 weeks in favour of EFV but
no differences in the critical outcomes drug resistance and
discontinuation due to adverse events. In addition, there
were significant differences in some adverse events favouring EFV over LPV/r.
RPV has been compared directly with EFV in RCTs
[15–17]. With respect to critical virological outcomes there
was no difference in virological suppression but there were
differences in drug resistance (RR 0.38, 95% CI 0.20–0.72;
P = 0.003) and virological failure (RR 0.55, 95% CI 0.29–
1.02; P = 0.06), both in favour of EFV. Pooled analyses by
the investigators of the two RCTs showed the risk of virological failure with RPV was highest in patients with a
baseline VL >100 000 copies/mL [17]. For critical safety
outcomes there was a difference in the proportion discontinuing for adverse events in favour of RPV (RR 2.29, 95%
CI 1.15–4.57; P = 0.02) but no difference in serious adverse
events. RPV also had better lipid profile outcomes.
The StAR study showed overall noninferiority of the
fixed-dose combination of TDF/FTC/RPV to fixed-dose
TDF/FTC/EFV at 48 weeks. In a subgroup analysis in
patients with baseline viral load less than 100 000 copies/
mL, superiority of the RPV-based regimen was demonstrated. Similarly to ECHO and THRIVE, StAR confirmed
higher rates of virological failure on RPV at high viral
loads (greater than 100 000 copies/mL) but not at lower
baseline viral load (less than 100 000 copies/mL). Because
rilpivirine is currently licensed for use only in patients with
baseline viral loads of <100 000 copies/mL, we believe that
at present it should remain as an alternative third-line
agent. However, in all three studies there was a lower
incidence of neuropsychiatric adverse events with RPV
than with EFV. RPV may be useful for individuals with
viral loads below 100 000 copies/mL, where concerns about
neuropsychiatric side effects are paramount, but it is
important that patients given this drug can both comply
with the dietary requirements and avoid acid-reducing
agents. It is important to note that there are very few data
regarding the administration of RPV with an ABC/3TC
NRTI backbone.
Since the 2012 guidelines were published, the fixed dose
combination of TDF/FTC/ELV/COBI (Stribild) has received
licensing approval. The two pivotal studies have compared
this regimen to fixed-dose TDF/FTC/EFV (GS-102) and
TDF/FTC with ATV/r (GS-103) [18,19] (see Appendix 4).
Virological failure rates have not been reported for these
studies but discontinuations for ‘lack of efficacy’ were
similar in both arms of each study. Since these studies
demonstrate non-inferiority of Stribild to both EFV and
ATV/r, both of which are currently preferred third agents, it
the view of the Writing Committee that Stribild should also
be a preferred option for first-line therapy. In addition
Stribild may confer some advantages in terms of its toxicity profile, although there are multiple potential drug–
drug interactions.
In summary, it is the view of the Writing Group that EFV,
given its performance across multiple well-controlled randomized trials and the wealth of clinical experience, should
remain a preferred third agent. In addition, because of
similar critical treatment outcomes, it is the view of the
Writing Group that ATV/r, DRV/r, RAL and ELV/COBI are
also recommended as preferred third agents.
RPV is also recommended as a preferred third agent but
only in patients with baseline VL <100 000 copies/mL.
As in the 2008 BHIVA treatment guidelines [1], NVP
remains an alternative third agent, based on the associated CD4 cell count restrictions that limit its use plus the
higher risk of moderate-to-severe rash/hepatitis and discontinuation for adverse events compared with other
agents [23,24].
LPV/r is listed as an alternative third agent based on
comparison of virological outcomes with EFV [2,3] and
DRV/r [20,21], which have been previously discussed.
FPV/r is also listed as an alternative third agent as it has
been shown to be non-inferior to LPV/r in terms of virological efficacy [25].
When selecting a third agent from either the preferred or
alternative options, factors such as potential side effects,
dosing requirements, dosing convenience, patient preference, co-morbidities, drug interactions and cost should be
considered.
Neuropsychiatric side effects have commonly been
reported in patients treated with EFV and patients with a
history of psychiatric disorders appear to be at a greater
risk of serious psychiatric adverse events [26]. In patients
with a current or a history of psychiatric disorders,
including depression, anxiety and suicidal ideation,
caution should be exercised in prescribing EFV and
strong consideration given to using an acceptable alternative third agent.
EFV may be used in pregnancy and the reader is directed
to the BHIVA guidelines for the management of HIV infection in pregnant women 2012 [27], for full discussion on
this issue. Further discussion of the choice of ART in
selected populations is outlined in Section 8 (ART in specific populations).
Saquinavir/ritonavir (SQV/r) is not listed as a preferred or
alternative option in the treatment of ART-naïve patients
with chronic infection. This is because of a higher pill
burden, the availability of alternative PI/rs and a recent
update to the summary of product characteristics requiring
dose escalation and careful ECG monitoring due to its
association with QT interval prolongation. SQV/r has been
reported as non-inferior to LPV/r in terms of virological
and safety outcomes [28].
The CCR5 antagonist MVC and unboosted ATV are not
licensed in Europe for initial ART and as such are not
recommended.
5.4.4 References
1 Gazzard BG, on behalf of the BHIVA Treatment Guidelines
Writing Group. BHIVA guidelines for the treatment of
2
3
4
5
HIV-1-infected adults with antiretroviral therapy 2008. HIV
Med 2008; 9: 563–608.
Riddler SA, Haubrich R, DiRienzo AG et al. for the AIDS
Clinical Trials Group Study A5142 Team. Class-sparing
regimens for initial treatment of HIV-1 infection. N Engl J
Med 2008; 358: 2095–2106.
Sierra-Madero J, Villasis-Keever A, Mendez P et al.
Prospective randomised open label trial of efavirenz vs
lopinavir/rit HIV+ treatment naïve subjects with CD4+
<200 cell/mm3. J Acquir Immune Defic Syndr 2010; 53:
582–588.
Puls RL, Srasuebkul P, Petoumenos K et al. Efavirenz versus
boosted atazanavir or zidovudine and abacavir in
antiretroviral treatment-naive, HIV-infected subjects: week
48 data from the Altair study. Clin Infect Dis 2010; 51:
855–864.
Winston A, Duncombe C, Li PC et al. Does choice of
combination antiretroviral therapy (cART) alter changes in
cerebral function testing after 48 weeks in treatment-naive,
HIV-1-infected individuals commencing cART? A
randomized, controlled study. Clin Infect Dis 2010; 50:
920–929.
6 Sax PE, Tierney C, Collier AC et al. Abacavir–lamivudine
versus tenofovir–emtricitabine for initial HIV-1 therapy. N
Engl J Med 2009; 361: 2230–2240.
7 Sax PE, Tierney C, Collier AC et al. Abacavir/lamivudine
versus tenofovir DF/emtricitabine as part of combination
regimens for initial treatment of HIV: final results. J Infect
Dis 2011; 204: 1191–1201.
445–456.
9 McComsey GA, Kitch D, Daar ES et al. Bone mineral density
and fractures in antiretroviral-naive persons randomized to
receive abacavir-lamivudine or tenofovir disoproxil
fumarate-emtricitabine along with efavirenz or atazanavirritonavir: AIDS Clinical Trials Group A5224s, a Substudy of
ACTG A5202. J Infect Dis 2011; 203: 1791–1801.
10 McComsey GA, Kitch D, Sax PE et al. Peripheral and central
fat changes in subjects randomized to abacavir-lamivudine
or tenofovir-emtricitabine with atazanavir-ritonavir or
efavirenz: ACTG Study A5224s. Clin Infect Dis 2011; 53:
185–196.
11 Lennox JL, DeJesus E, Lazzarin A et al. Safety and efficacy
of raltegravir-based versus efavirenz-based combination
therapy in treatment-naive patients with HIV-1 infection: a
multicentre, double-blind randomised controlled trial. Lancet
2009; 374: 796–806.
12 Lennox JL, Dejesus E, Berger DS et al. Raltegravir versus
efavirenz regimens in treatment-naive HIV-1-infected
patients: 96-week efficacy, durability, subgroup, safety, and
metabolic analyses. J Acquir Immune Defic Syndr 2010; 55:
39–48.
13 Markowitz M, Nguyen BY, Gotuzzo E et al. Sustained
antiretroviral effect of raltegravir after 96 weeks of
combination therapy in treatment-naive patients with
HIV-1 infection. J Acquir Immune Defic Syndr 2009; 52:
350–356.
14 Gotuzzo E, Nguyen B-Y, Markowitz M et al. Sustained
efficacy and tolerability of raltegravir after 240 weeks of
combination ART in treatment-naïve HIV-1 infected
patients: final analysis of Protocol 004. 6th IAS on HIV
Pathogenesis, Treatment and Prevention. Rome, Italy. July
2011 [Abstract WEPDB0102].
15 Molina JM, Cahn P, Grinsztejn B et al. Rilpivirine versus
efavirenz with tenofovir and emtricitabine in treatmentnaive adults infected with HIV-1 (ECHO): a phase 3
randomised double-blind active-controlled trial. Lancet 2011;
378: 238–246.
16 Cohen CJ, Andrade-Villanueva J, Clotet B et al. Rilpivirine
versus efavirenz with two background nucleoside or
nucleotide reverse transcriptase inhibitors in treatment-
of HIV infection over 48 weeks: a randomised
non-inferiority trial. Lancet 2006; 368: 476–482.
26 Efavirenz Summary of Product Characteristics (27 July
naive adults infected with HIV-1 (THRIVE): a phase 3,
2011). Electronic Medicines Compendium. Available at
randomised, non-inferiority trial. Lancet 2011; 378:
http://www.medicines.org.uk/emc/medicine/11284 (accessed
229–237.
17 Cohen C, Molina JM, Cahn P et al. Pooled week 48 efficacy
April 2012).
27 Taylor GP, Clayden P, Dhar J et al. BHIVA guidelines
and safety results from ECHO and THRIVE, two double-
for the management of HIV infection in pregnant
blind, randomised phase III trials comparing TMC278 versus
efavirenz in treatment-naïve HIV-1-infected patients. 18th
women 2012. HIV Med 2012; 13 (Suppl. 2):
87–157.
International AIDS Conference. Vienna, Austria. July 2010
[Abstract THLBB206].
18 Zolopa A, Sax PE, DeJesus E et al. for the GS-US-236-0102
Study Team. A randomized double-blind comparison of
28 Walmsley S, Avihingsanon A, Slim J et al. Gemini:
a noninferiority study of saquinavir/ritonavir versus
lopinavir/ritonavir as initial HIV-1 therapy in adults.
J Acquir Immune Defic Syndr 2009; 50: 367–374.
coformulated elvitegravir/cobicistat/emtricitabine/tenofovir
disoproxil fumarate versus efavirenz/emtricitabine/tenofovir
disoproxil fumarate for initial treatment of HIV-1 infection:
analysis of week 96 results. J Acquir Immune Defic Syndr
2013; 63: 96–100.
19 Rockstroh JK, DeJesus E, Henry K et al. for the GS-236-0103
Study Team. A randomized, double-blind comparison of
coformulated elvitegravir/cobicistat/emtricitabine/tenofovir
DF vs ritonavir-boosted atazanavir plus coformulated
emtricitabine and tenofovir DF for initial treatment of HIV-1
infection: analysis of week 96 results. J Acquir Immune
Defic Syndr 2013; 62: 483–486.
20 Ortiz R, Dejesus E, Khanlou H et al. Efficacy and safety of
once-daily darunavir/ritonavir versus lopinavir/ritonavir in
treatment-naive HIV-1-infected patients at week 48. AIDS
2008; 22: 1389–1397.
21 Mills AM, Nelson M, Jayaweera D et al. Once-daily
darunavir/ritonavir vs. lopinavir/ritonavir in treatmentnaive, HIV-1-infected patients: 96-week analysis. AIDS
2009; 23: 1679–1688.
22 Nelson M, Girard PM, Demasi R et al. Suboptimal adherence
to darunavir/ritonavir has minimal effect on efficacy
compared with lopinavir/ritonavir in treatment-naive,
HIV-infected patients: 96 week ARTEMIS data. J Antimicrob
Chemother 2010; 65: 1505–1509.
23 van Leth F, Phanuphak P, Ruxrungtham K et al. Comparison
of first-line antiretroviral therapy with regimens including
nevirapine, efavirenz, or both drugs, plus stavudine and
lamivudine: a randomised open-label trial, the 2NN Study.
Lancet 2004; 363: 1253–1263.
24 Soriano V, Arastéh K, Migrone H et al. Nevirapine versus
atazanavir/ritonavir, each combined with tenofovir
disoproxil fumarate/emtricitabine, in antiretroviral-naive
HIV-1 patients: the ARTEN Trial. Antivir Ther 2011; 16:
339–348.
25 Eron J Jr, Yeni P, Gathe J Jr et al. The KLEAN study of
fosamprenavir-ritonavir versus lopinavir-ritonavir, each in
combination with abacavir-lamivudine, for initial treatment
5.5 Novel antiretroviral therapy strategies
• We recommend against the use of PI monotherapy as
initial therapy for treatment-naïve patients (1C).
5.5.2 Rationale
Data on use of PI monotherapy as initial ART are limited.
In one RCT comparing LPV/r vs. LPV/r plus ZDV and 3TC,
the use of PI monotherapy as initial ART was associated
with lower rates of virological suppression at 48 weeks
and with the emergence of PI mutations [1]. There were
no significant differences in tolerability. For this reason,
PI monotherapy is not recommended as initial ART.
However, as with other novel strategies there may be
specific circumstances where a rationale for its use may be
made.
5.5.3 Reference
1 Delfraissy JF, Flandre P, Delaugerre C et al.
Lopinavir/ritonavir monotherapy or plus zidovudine and
lamivudine in antiretroviral-naïve HIV-infected patients. AIDS
2008; 22: 385–393.
• We recommend against the use of PI-based dual ART
with a single NRTI, NNRTI, CCR5 receptor antagonist or
INI as an initial therapy for treatment-naïve patients
(1C).
5.5.5 Rationale
A number of studies have assessed the use of PI-based dual
ART as initial therapy in treatment-naïve patients. Many of
these are either open label (not powered to demonstrate
non-inferiority compared with triple therapy), singlearm studies or have only been reported as conference
abstracts.
The combination of an NNRTI with a PI/r has been
shown to have similar virological efficacy compared with
triple-combination regimens in one study [1]. There were
no significant differences in time to either virological or
regimen failure with a combination of LPV/r and EFV
compared with either two NRTIs and EFV or two NRTIs and
LPV/r. There was, however, an increased rate of drug resistance in the NRTI-sparing arm, with the emergence of more
NNRTI-associated resistance mutations than the comparator arms. An increased rate of grade 3/4 toxicities was
observed, predominantly low-density lipoprotein cholesterol and triglyceride elevations.
Comparison of a dual-therapy regimen containing one
NRTI with a PI/r (TDF and LPV/r vs. two NRTIs and LPV/r)
failed to demonstrate non-inferiority of the dual-therapy
arm compared with a standard triple-therapy combination
[2].
The use of dual therapy with the CCR5-receptor antagonist MVC in combination with a PI/r has been assessed in
one RCT but was not designed to show non-inferiority [3].
The comparative efficacy of the INI RAL plus a PI/r is being
compared with standard triple therapy in several ongoing
and/or unpublished studies [4–8]. Reports from one study
[4,5] suggest similar rates of virological suppression at 48
and 96 weeks. However, in a single-arm study investigating RAL in combination with DRV/r, a significantly
increased risk of virological failure with emergent INI
resistance was seen in patients with baseline VL >100 000
copies/mL compared with those with a baseline VL
< 100 000 copies/mL [9]. Further data are required and
there is a need to await the results of ongoing randomized
trials.
5.5.6 References
1 Riddler SA, Haubrich R, DiRienzo AG et al. for the AIDS
Clinical Trials Group Study A5142 Team. Class-sparing
regimens for initial treatment of HIV-1 Infection. N Engl J
Med 2008; 358: 2095–2106.
2 Lazzarin PM, Antinori A, Carosi G et al. Lopinavir/ritonavir +
tenofovir dual therapy versus lopinavir/ritonavir-based triple
therapy in HIV-infected antiretroviral naïve subjects: the
Kalead Study. J Antivir Antiretrovir 2010; 2: 056–062.
doi:10.4172/jaa.1000024.
3 Portsmouth S, Craig C, Mills A et al. 48-week results of
once-daily maraviroc (MVC) 150 mg in combination with
ritonavir-boosted atazanavir (ATV/r) compared to
emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve
patients infected with R5 HIV-1 (Study A4001078). 6th IAS
Conference on HIV Pathogenesis, Treatment and Prevention.
Rome, Italy. July 2011 [Abstract TUAB0103].
4 Reynes J, Adebayo L, Pulido F et al. Examination of
noninferiority, safety, and tolerability of lopinavir/ritonavir
and raltegravir compared with lopinavir/ritonavir and
tenofovir/emtricitabine in antiretroviral naive subjects: the
PROGRESS study, 48 week results. HIV Clin Trials 2011; 12:
255–267.
5 Soto-Malave R, Lawal A, Reynes J et al. Lopinavir/ritonavir
(LPV/r) combined with raltegravir (RAL) or tenofovir/
emtricitabine (TDF/FTC) in antiretroviral-naïve subjects:
96-week efficacy and safety results of the PROGRESS Study.
XV Congreso Panamericano de Infectología. Punta del Este,
Uruguay. April 2011.
6 Bowman V, Rieg G, Jain S et al. 48 week results of a pilot
randomized study of a nucleoside reverse transcriptase
inhibitor (NRTI)-sparing regimen of raltegravir (RAL) +
lopinavir/ritonavir (LPV/r) versus efavirenz/tenofovir
disoproxil fumarate/emtricitabine (EFV/TDF/FTC) in
antiretroviral-naïve patients: CCTG 589. 6th IAS Conference
on HIV Pathogenesis, Treatment and Prevention. Rome, Italy.
July 2011 [Abstract CDB336].
7 Bedimo R, Drechsler H, Cutrell J et al. RADAR study:
raltegravir combined with boosted darunavir has similar
safety and antiviral efficacy as tenofovir/emtricitabine
combined with boosted darunavir in antiretroviral-naïve
patients. 6th IAS Conference on HIV Pathogenesis,
Treatment and Prevention. Rome, Italy. July 2011 [Abstract
MOPE214].
8 French National Agency for Research on AIDS and Viral
Hepatitis, NEAT–European AIDS Treatment Network. An
open-label randomised two-year trial comparing two first-line
regimens in HIV-infected antiretroviral naïve subjects:
darunavir/r + tenofovir/emtricitabine vs. darunavir/r +
raltegravir (ANRS 143/NEAT 001). Available at
http://clinicaltrials.gov/ct2/show/NCT01066962 (accessed April
2012).
9 Taiwo B, Zheng L, Gallien S et al.; ACTG A5262 Team.
Efficacy of a nucleoside-sparing regimen of
darunavir/ritonavir plus raltegravir in treatment-naive
HIV-1-infected patients (ACTG A5262). AIDS 2011; 25:
2113–2122.
6.0 Supporting patients on therapy
6.1 Adherence
6.1.1 Interventions to increase adherence
to treatment
6.1.1.1 Recommendations
• We recommend adherence and potential barriers to it are
assessed and discussed with the patient whenever ART is
prescribed or dispensed (GPP).
• We recommend adherence support should address both
perceptual barriers (e.g. beliefs and preferences) and/or
practical barriers (e.g. limitations in capacity and
resources) to adherence (GPP).
Auditable measures
• Record in patient’s notes of discussion and assessment of
adherence and potential barriers to, before starting a
new ART regimen and while on ART.
• Record in patient’s notes of provision or offer of adherence support.
6.1.1.2 Rationale
Low adherence to ART is associated with drug resistance,
progression to AIDS [1] and death [2–4]. Given the
multiple adverse consequences of treatment failure
(risk of disease progression, increase in complexity
and costs of treatment, and risk of HIV transmission)
engaging patients in treatment decisions and the monitoring and support of adherence are of paramount
importance [5] (see Section 3: Patient involvement in
decision-making).
Non-adherence is best understood as a variable behaviour with intentional and unintentional causes. Most
people taking medication are non-adherent some of the
time. Unintentional non-adherence is linked to limitations
in capacity or resources that reduce the ability to adhere to
the treatment as intended. Intentional non-adherence is the
product of a decision informed by beliefs, emotions and
preferences [6].
BHIVA recommendations on the monitoring of adherence to ART are available [7]. NICE has published
detailed guidance on the assessment and support of
adherence to medication in chronic diseases; key recommendations for adherence support are shown in Box 6.1
[8].
6.1.2 Should the choice of first-line antiretroviral therapy
combination be affected by risk of non-adherence?
6.1.2.1 Recommendation
• In patients where there is clinical concern that doses
may be missed intermittently, there is insufficient evidence to recommend a PI/r over EFV-based regimens.
However, where there is a risk of frequent prolonged
treatment interruptions, EFV-based regimens may be
associated with more frequent selection for drug resistance compared with PI/r.
6.1.2.2 Rationale
Clinicians are poor at both predicting future adherence to
ART in naïve subjects [11] and at detecting non-adherence
during ART [12,13]. However, in a case where a clinician or
patient has concerns about a patient’s future adherence,
should this influence the choice of first-line therapy?
The consequences of low adherence depend on drug
pharmacokinetics, potency, fitness of resistant strains and
genetic barrier to resistance [14]. Hence, both the level and
pattern of non-adherence must be considered.
Large RCTs of first-line therapy may not be able to
inform this choice as subjects likely to be non-adherent are
often excluded from such trials. On the other hand, observational studies often select patients already established on
ART [15,16] where the observed effects of non-adherence
on treatment outcome are likely to differ from those in
patients starting ART de novo. This selection bias may
exclude those who have either experienced early virological failure, disease progression (or even death) or have
defaulted from care. In addition, most studies either predate the use of boosted-PI regimens in first-line therapy
[15,17] or include large numbers of patients on unboosted
PI regimens.
Three different outcomes may be considered: virological
suppression, selection of drug resistance, and effect of
pattern of non-adherence.
Effect of adherence on viral suppression. There are
no data from RCTs that directly address this question.
Among subjects reporting <95% adherence in a RCT comparing LPV/r with once-daily DRV/r, virological failure
was more likely in the LPV/r arm [18].
Among patients who were virologically suppressed initially, adherence <95% was associated with an increased
Box 6.1 Summary of NICE guidance on adherence support [8]
• A ‘no-blame’ approach is important to facilitate open and honest discussion.
• A patient’s motivation to start and continue with prescribed medication is influenced by the way in which they judge
their personal need for medication (necessity beliefs), relative to their concerns about potential adverse effects.
Delayed uptake and non-adherence are associated with doubts about personal need for ART and concerns about
taking it [9,10].
• Interventions to support adherence should be individualized to address specific relevant perceptual and practical
barriers. A three-step ‘Perceptions and Practicalities Approach’ [9] may be helpful:
1. Identify and address any doubts about personal need for ART.
2. Identify and address specific concerns about taking ART.
3. Identify and address practical barriers to adherence.
• Because evidence is inconclusive, only use interventions to overcome practical problems if there is a specific need.
Interventions might include:
䊊 suggesting patients record their medicine-taking;
䊊 encouraging patients to monitor their results;
䊊 simplifying the dosing regimen;
䊊 using a multicompartment medicines system;
䊊 If side effects are a problem:
• discuss benefits and long-term effects and options for dealing with side effects;
• consider adjusting the dosage, switching to another combination or other strategies such as changing the dose
timing or formulation.
• Patients’ experience of taking ART and their needs for adherence support may change over time.
䊊 patients’ knowledge, understanding and concerns about medicines and the benefits they perceive should be
reviewed regularly at agreed intervals.
risk of failure [16], and very low adherence (<50%) results
in virological rebound irrespective of regimen [5,16,19].
However, virological suppression has been observed with
only moderate adherence (50–75%) among patients on
NNRTIs [5,16,19] and virological failure has been reported
to be significantly more likely among all patients on
unboosted PI-based regimens where adherence was <95%
[16]. However, this finding may have been confounded by
the once-daily dosing in the EFV group. A further study
[20] examined only patients with undetectable viraemia
and found no difference in rates of virological rebound for
patients on PI/r vs. NNRTIs.
Effect of adherence on selection of drug resistance.
The effect of level of non-adherence on selection of drug
resistance varies by class. This was first described for
unboosted PI regimens where moderate-to-high adherence
was associated with increased risk of resistance [21]. The
incidence of resistance in studies of boosted-PI regimens is
low [18,22–26] but is observed with adherence just below
80–95% [15,27]. In contrast, for first-generation NNRTIs
the selection for resistance has been associated with very
low average adherence (<50%) [14,28].
Effect of pattern of non-adherence. The pattern of
non-adherence may also be important. A number of small
observational studies have examined short intermittent
treatment interruptions (2–7 days) in patients with prolonged virological suppression. For EFV, cycles of 2 days
off per week appeared no more likely to result in treatment
failure than continuous therapy, as long as the treatment
interruption was not prolonged [29,30]. However, cycles of
7- or 28-day treatment interruption resulted in failure of
EFV and selection of resistance [31,32]. For PI/r, one study
found that average adherence, rather than duration of
treatment interruption, was associated with virological
response [33].
6.1.3 Dosing frequency
A recent overview of systematic reviews of consumeroriented medication interventions found that simplified
dosing regimens improved adherence in the majority of
studies in several reviews [34]. Another review of adherence interventions found that reducing dosing to once
daily had some effect on adherence but no effect on
treatment outcome was observed [35]. NICE [8] reviewed
several RCTs of interventions to reduce dose frequency
and found that adherence may increase with once-daily
dosing. For ART regimens, a meta-analysis of once- vs.
twice-daily ART regimens found that in the subgroup of
treatment-naïve trials, once-daily ART was associated
with a significantly improved adherence and virological
outcome [36].
Therefore, once-daily dosing is a reasonable intervention
to reduce unintentional non-adherence to ART.
6.1.4 Fixed-dose combinations
In examining whether fixed-dose combination formulations (FDCs) of drugs improve adherence or treatment
outcome, only studies comparing the same drugs with the
same dose frequency given as combination or separate pills
were considered. No meta-analyses have been published on
this subject for ART. A meta-analysis of nine RCTs and
cohort studies in a range of diseases found the use of FDCs
was associated with a significant reduction in the risk of
non-adherence [36]. Gupta et al. [37] reported a metaanalysis of cohort studies and found that use of FDCs
for antihypertensives was associated with increased adherence but with no improvement on the control of blood
pressure.
There are no published studies in HIV therapy directly
comparing outcomes with FDCs versus separate agents.
A retrospective study of a pharmacy database found
no benefit in persistence on first-line ART for any FDC
over separate agents [38]. In the ECHO/ THRIVE studies
a lower virological response rate in patients with baseline
VL >100 000 copies was observed for RPV- versus EFVbased regimens when dosed as separate agents [39]; this
was not repeated when formulated as FDCs in the preliminary 48-week results from the STaR study [40]. Although
the use of FDCs may have driven this apparent improvement in performance of RPV, it may also have arisen due to
the simpler once-daily regimens in STaR, other methodological differences or by chance.
A further advantage of FDCs is that they prevent patients
from preferentially adhering less closely to one component
of a regimen than others. A minority of patients in one
study did report such ‘differential’ adherence, but this was
not associated with outcome for currently used first-line
strategies [41].
An observational study of outcomes following a switch
from Atripla to multi-tablet regimens provides very low
quality evidence that this may not result in an increase in
virological failures [42]. However, the data are available in
abstract only and raise methodological questions. In view
of the higher quality evidence in support of FDCs and the
implications and costs of treatment failure, there is insufficient evidence to support this strategy at present.
In summary FDCs support adherence to treatment, and
this may well reduce the risk of virological failure.
However, the size of this effect is yet to be defined.
6.1.5 References
1 Bangsberg DR, Perry S, Charlebois ED et al. Non-adherence
to highly active antiretroviral therapy predicts progression to
AIDS. AIDS 2001; 15: 1181–1183.
2 Garcia de OP, Knobel H, Carmona A et al. Impact of
adherence and highly active antiretroviral therapy on
survival in HIV- infected patients. J Acquir Immune Defic
Syndr 2002; 30: 105–110.
3 Hogg RS, Heath K, Bangsberg D et al. Intermittent use of
triple-combination therapy is predictive of mortality at
baseline and after 1 year of follow-up. AIDS 2002; 16:
1051–1058.
4 Lima VD, Geller J, Bangsberg DR et al. The effect of
adherence on the association between depressive symptoms
and mortality among HIV-infected individuals first initiating
HAART. AIDS 2007; 21: 1175–1183.
5 Bangsberg DR. A paradigm shift to prevent HIV drug
resistance. PLoS Med 2008; 5: e111.
6 Horne R, Weinman J, Barber N, Elliott RA, Morgan M.
Concordance, Adherence and Compliance in Medicine
Taking: A Conceptual Map and Research Priorities. London,
National Institute for Health Research (NIHR) Service
Delivery and Organisation (SDO) Programme, 2005.
Available at http://www.netscc.ac.uk/hsdr/files/project/
SDO_FR_08-1412-076_V01.pdf (accessed May 2012).
April 2012).
8 Nunes V, Neilson J, O’Flynn N et al. Clinical Guidelines and
Evidence Review for Medicines Adherence: Involving Patients
in Decisions about Prescribed Medicines and Supporting
Adherence. London, National Collaborating Centre for
Primary Care and Royal College of General Practitioners,
2009.
9 Horne R, Cooper V, Gellaitry G, Date HL, Fisher M. Patients’
perceptions of highly active antiretroviral therapy in relation
to treatment uptake and adherence: the utility of the
necessity-concerns framework. J Acquir Immune Defic Syndr
2007; 45: 334–341.
10 Gonzalez JS, Penedo FJ, Llabre MM et al. Physical
symptoms, beliefs about medications, negative mood, and
long-term HIV medication adherence. Ann Behav Med 2007;
34: 46–55.
11 Gross R, Bilker WB, Friedman HM, Coyne JC, Strom BL.
Provider inaccuracy in assessing adherence and outcomes
lopinavir/ritonavir as initial HIV-1 therapy in
with newly initiated antiretroviral therapy. AIDS 2002; 16:
adults. J Acquir Immune Defic Syndr 2009; 50:
367–374.
1835–1837.
12 Bangsberg D, Hecht F, Clague H et al. Provider assessment
of adherence to HIV antiretroviral therapy. J Acquir Immune
25 Riddler SA, Haubrich R, DiRienzo AG et al. Class-sparing
regimens for initial treatment of HIV-1 infection. N Engl J
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13 Miller LG, Liu H, Hays RD et al. How well do clinicians
estimate patients’ adherence to combination antiretroviral
26 Molina JM, Andrade-Villanueva J, Echevarria J et al.;
CASTLE Study Team. Once-daily atazanavir/ritonavir versus
twice-daily lopinavir/ritonavir, each in combination with
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14 Gardner EM, Burman WJ, Steiner JF et al. Antiretroviral
medication adherence and the development of class-specific
tenofovir and emtricitabine, for management of
antiretroviral-naive HIV-1-infected patients: 48 week
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15 Bangsberg DR, Acosta EP, Gupta R et al.
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non-nucleoside reverse transcriptase inhibitors explained by
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treatment of HIV-1: a randomized trial. Ann Intern Med
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16 Maggiolo F, Airoldi M, Kleinloog HD et al. Effect of
adherence to HAART on virologic outcome and on the
selection of resistance-conferring mutations in NNRTI- or
PI-treated patients. HIV Clin Trials 2007; 8: 282–292.
17 Trotta MP, Ammassari A, Cozzi-Lepri A et al. Adherence to
highly active antiretroviral therapy is better in patients
receiving non-nucleoside reverse transcriptase inhibitorcontaining regimens than in those receiving protease
inhibitor-containing regimens. AIDS 2003; 17: 1099–1102.
18 Nelson M, Girard PM, DeMasi R et al. Suboptimal adherence
to darunavir/ritonavir has minimal effect on efficacy
compared with lopinavir/ritonavir in treatment-naïve
HIV-infected patients: 96 week ARTEMIS data. J Antimicrob
2011; 154: 445–456.
28 King MS, Brun SC, Kempf DJ. Relationship between
adherence and the development of resistance in
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lopinavir/ritonavir or nelfinavir. J Infect Dis 2005; 191:
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29 Cohen CJ, Colson AE, Sheble-Hall AG, McLaughlin KA,
Morse GD. Pilot study of a novel short-cycle antiretroviral
treatment interruption strategy: 48-week results of the
five-days-on, two-days-off (FOTO) study. HIV Clin Trials
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30 Reynolds SJ, Kityo C, Hallahan CW et al. A randomized,
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20 Bangsberg DR. Less than 95% adherence to nonnucleoside
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6.2 Pharmacology
More than for any other infection, patients receiving ART
require their doctor to have a clear understanding of the
basic principles of pharmacology to ensure effective and
appropriate prescribing. This is especially the case in four
therapeutic areas.
6.2.1 Drug interactions
• We recommend that potential adverse pharmacokinetic
interactions between ARV drugs and other concomitant
medications are checked before administration (with
tools such as http://www.hiv-druginteractions.org)
(GPP).
Auditable measure. Record in patient’s notes of
potential adverse pharmacokinetic interactions between
ARV drugs and other concomitant medications.
6.2.1.2 Rationale
The importance of considering the potential for drug
interactions in patients receiving ART cannot be overemphasized. DDIs may involve positive or negative interactions between ARV agents or between these and drugs
used to treat other coexistent conditions. A detailed list is
beyond the remit of these guidelines but clinically important interactions to consider when co-administering with
ARV drugs include interactions with the following drugs:
methadone, oral contraceptives, anti-epileptics, antidepressants, lipid-lowering agents, acid-reducing agents,
certain antimicrobials (e.g. clarithromycin, minocycline
and fluconazole), some anti-arrhythmics, TB therapy, anticancer drugs, immunosuppressants, phosphodiesterase
inhibitors and anti-HCV therapies. Most of these interactions can be managed safely (i.e. with/without dosage
modification, together with enhanced clinical vigilance)
but in some cases (e.g. rifampicin and PIs, proton pump
inhibitors and ATV, and didanosine and HCV therapy) the
nature of the interaction is such that co-administration
must be avoided.
Importantly, patient education on the risks of drug interactions, including over-the-counter or recreational drugs,
should be undertaken and patients should be encouraged to
check with pharmacies or their healthcare professionals
before commencing any new drugs, including those prescribed in primary care.
Large surveys report that about one-in-three-to-four
patients receiving ART is at risk of a clinically significant
drug interaction [1–6]. This suggests that safe management of HIV drug interactions is only possible if medication recording is complete, and if physicians are aware
of the possibility that an interaction might exist. Incomplete or inaccurate medication recording has resulted
from patient self-medication, between hospital and community health services [7] and within hospital settings
particularly when multiple teams are involved, or when
medical records are fragmented (e.g. with separate HIV
case notes) [8].
More worryingly, one survey in the UK reported that
even when medication recording is complete, physicians
were only able to identify correctly one-third of clinically
significant interactions involving HIV drugs [4]. In addition to HIV specialist and local drug information pharmacists, the University of Liverpool’s comprehensive drug
interaction website (http://www.hiv-druginteractions.org)
is an excellent and highly recommended resource for information relating to potential drug interactions. Additional
information resources also include the electronic medicines compendium (http://www.medicines.org.uk/emc) and
medical information departments of pharmaceutical
companies.
Communication with GPs and other medical specialties
involved in patient care is fundamental in minimizing the
risk of adverse DDIs. All clinic letters should carry as a
standard header or footer advice to check for interactions, and links to resources, such as http://www.hivdruginteractions.org, to address the potential for drug
interactions.
6.2.2 Therapeutic drug monitoring
• We recommend against the unselected use of TDM (GPP).
• TDM may be of clinical value in specific populations
(e.g. children, pregnant women) or selected clinical scenarios (e.g. malabsorption, drug interactions, suspected
non-adherence to therapy).
6.2.2.2 Rationale
TDM has been shown to be valuable in optimizing the
management of certain patients; however, the general
utility of this test in patients receiving ART has been poorly
assessed. With the marked improvement in efficacy and
tolerability of modern ARV regimens, the role of TDM in
clinical management has also evolved. A Cochrane review
of RCTs [9] suggested little value when used unselectively.
However, TDM may aid the management of vulnerable
populations or complex clinical situations.
been recruited to pharmacokinetic studies at licensed
treatment doses that are known to be both safe and
efficacious.
(iii) Managing drug interactions (see above). Where the HIV
drug has the potential to be adversely affected by
another drug, and the combination is unavoidable,
TDM may be used either to manage that interaction, or
else discount a significant interaction in a particular
patient.
(iv) Other situations. Knowledge of plasma–drug concentrations may be clinically useful when evaluating
whether there is scope for treatment simplification, or
else confirming or refuting impaired drug absorption as
a reason for virological failure.
More detailed recommendations for the use of TDM are
available in the BHIVA guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals
2011 [10]. As for all other investigations, it is essential that
TDM is undertaken correctly, especially with regard to
timing (undertaken when steady state has been achieved).
A consensus has been achieved for defining targets [11] for
many ARVs. With many newer agents, evidence for a
defined minimum target for efficacy is either weak or
lacking, and evidence for an upper toxicity cut-off for most
ARVs is lacking.
6.2.3 Stopping therapy: pharmacological considerations
(i) Monitoring adherence. While detection of drug at
therapeutic or even high plasma concentrations does
not exclude low adherence, absence of measurable
drug, or else very low levels of drug, strongly suggest
lack of medication intake, particularly in the absence
of evidence of significant malabsorption. Here, TDM
should rarely be interpreted in isolation, but rather
integrated with virological rebound, particularly in the
absence of any resistance mutations and other features
in the history that suggest risk for low treatment
adherence.
(ii) Optimizing treatment in vulnerable patients (e.g. children, pregnant women and patients with extremes of
body mass index) or in specific clinical situations
(e.g. liver and renal impairment, treatment failure,
drug interactions both foreseen and unanticipated,
malabsorption, suspected non-adherence and unlicensed once-daily dosing regimens). In these scenarios, the aim is to optimize dosing based either on
known efficacy or toxicity cut-offs, or else to
achieve the range of plasma concentrations encountered in patients without these factors, who have
• We recommend patients stopping ART containing an
NNRTI in combination with an NRTI backbone replace
all drugs with a PI (LPV/r) for 4 weeks (1C).
• We recommend patients stopping a PI-containing
regimen stop all drugs simultaneously and no replacement is required (1C).
Auditable measure. Proportion of patients with an
undetectable VL on ART who, on stopping a regimen
containing an NNRTI in combination with a NRTI backbone, are switched to PI/r for 4 weeks.
6.2.3.2 Rationale
In general, treatment interruptions are not recommended
for most patients. Whatever the reason for stopping ART
(e.g. drug toxicity, intercurrent illness, after pregnancy or
patient choice), pharmacological issues must be considered for a clinician to give guidance. The half-life of each
drug included in the regimen is critical. There is the
potential for monotherapy or dual therapy if ARV drugs
with different half-lives are stopped simultaneously.
NNRTI and NRTI resistance mutations have been detected
following discontinuation of previously suppressive regimens [12] and may have the potential to affect the likelihood of viral re-suppression on restarting an NNRTIbased ART regimen.
There are limited data on which to base recommendations for how to protect against development of resistance in the period immediately following treatment
cessation. Several discontinuation strategies have been
proposed [13], and choice is influenced by clinical considerations, patient wishes and pharmacological principles. Options include: (i) simultaneously stopping all
drugs in a regimen containing drugs with similar halflives; (ii) a staggered stop, discontinuing the drug with
the longest half-life first in a regimen containing drugs
with short and long half-lives; or (iii) replacing all drugs
with a drug with a short half-life and high genetic barrier
to resistance (i.e. a PI). There is no randomized comparison of these three strategies. However, in one study a
lower number of emergent resistance mutations were seen
in patients switching to a PI compared with those undertaking a simultaneous or staggered stop [12]. Therapeutic
plasma concentrations of EFV can also be detected up to
3 weeks after stopping the drug in some patients and
thus a staggered stop of 1 week may potentially be inadequate to prevent emergence of NNRTI mutations [14].
The optimal duration of replacement with a PI is not
known, but 4 weeks is probably advisable.
6.2.4 Switching therapy: pharmacological considerations
Data on how to switch away from EFV to an alternative
‘third’ agent are either non-existent, or of low or very low
quality. Based on pharmacological principles, there is little
rationale for any strategy other than straightforward substitution when switching to a PI/r or RAL. Pharmacokinetic
studies show that straightforward substitution with ETV
and RPV may result in slightly lower concentrations of
either drug for a short period following switching, but
limited virological data suggest that risk of virological
failure with this strategy is low. Different strategies for
switching to NVP have been proposed, but no comparative
data are available to guide the choice of strategy. Limited
data suggest that the dose of MVC should be doubled in the
week following switching (unless given together with a
PI/r).
If switching away from EFV is undertaken when VL is
likely to still to be detectable (e.g. because of CNS intolerance within the first few weeks of starting EFV), substitution with a PI/r in preference to a within-class switch is
advised.
6.2.4.2 Rationale
Switching a component of an ART regimen is frequently
considered in patients to manage drug side effects or
address adherence issues. ARVs that either induce or
inhibit drug-metabolizing enzymes have the potential to
affect the plasma concentrations of the new agent. This
applies in particular to switching away from NNRTIs.
Induction of drug metabolizing enzymes by EFV is likely to
persist for a period beyond drug cessation. Consideration
should also be taken of whether or not VL is maximally
suppressed when planning how to switch away from EFV
to an alternative agent. Broadly, strategies for switching
from EFV to an alternative ‘third’ agent may be summarized as follows.
Efavirenz to nevirapine. A pharmacokinetic study
performed in HIV-positive individuals suggested that
patients changing from EFV to NVP should commence on
200 mg twice a day to ensure therapeutic plasma concentrations and potentially avoid selection of resistance to
NVP [15]. However, no patient in the NVP lead-in group
experienced virological failure in the 3-month follow-up
period. Switching without dose escalation is in direct contrast with the information in the Viramune summary of
product characteristics, which advises administration of a
NVP lead-in dose (200 mg once daily for 2 weeks) when
starting NVP [16], as this has been shown to decrease the
frequency of rash.
In ART-experienced patients who are virologically suppressed with an undetectable plasma HIV RNA level (<50
copies/mL), the risk of hypersensitivity and/or hepatotoxicity on switching to NVP is not increased in patients with
higher CD4 cell counts (above the gender-specific CD4 cell
count thresholds) [17]. In ART-experienced patients with
detectable plasma HIV RNA levels, a switch to NVP is not
advised.
Furthermore, the need to minimize any window for
developing resistance is greatest in patients who discontinue EFV early on when virological suppression has not
yet been achieved. The latter scenario is made more
complex when enzyme induction has not yet been fully
achieved, and if doubt exists, alternatives to switch to
should be considered.
Efavirenz to etravirine. Steady-state (14 days following the switch) ETV pharmacokinetic parameters are
lowered by previous EFV intake in the case of both oncedaily (Cmin was lowered by 33%) and twice-daily (Cmin was
lowered by 37%) administration. However, ETV concentrations have been shown to increase over time following the
switch and in patients with undetectable VLs switching from
EFV to ETV, standard doses of ETV can be commenced [18].
To date, no data are available on what strategy to adopt in
patients with active viral replication.
3 Marzolini C, Elzi L, Gibbons S et al.; Swiss HIV Cohort
Study. Prevalence of co-medications and impact of potential
drug-drug interactions in the Swiss HIV Cohort Study.
Efavirenz to rilpivirine. Concentrations of RPV are
lowered by previous EFV administration. However, 28
days after the switch, they returned to levels comparable
with those when RPV was administered without previous
EFV treatment, except for a 25% lower Cmin. Therefore, in
patients with undetectable VLs switching from EFV to
RPV, standard doses of RPV can be commenced [19]. To
date, no data are available on what strategy to adopt in
patients with active viral replication.
Efavirenz to a ritonavir-boosted protease inhibitor.
Because of the strong inhibitory effect of ritonavir on
CYP450 3A4, it is unlikely to require a modification of the
PI/r dose when switching from EFV to PI/r. Formal pharmacokinetic data are unavailable. TDM data were presented on ATV/r and showed that after stopping EFV, ATV
concentrations were above the suggested minimum effective concentration in all studied subjects [20].
Efavirenz to raltegravir. Although formal pharmacokinetic data are not available, switching EFV to RAL
should not lead to clinically significant consequences, as
co-administration of EFV with RAL led to a moderate-toweak reduction in RAL Cmin (21%) [21], which may persist
for 2–4 weeks, after the switch but the degree of this
reduction is unlikely to be clinically meaningful.
Efavirenz to maraviroc. A formal pharmacokinetic
study in HIV-positive individuals showed that the induction effect of EFV necessitated an increase in MVC dose to
600 mg twice daily for 1 week following the switch [22].
MVC 300 mg twice daily (standard dose) seems to be safe
after this period. Although there is an absence of data,
when switching from EFV to MVC plus a PI/r, it is likely
that a dose of 150 mg twice daily is safe from the first day
after the switch. Whether it is advisable to use MVC 150 mg
once daily in this context or for how long a twice-daily
dose should be used after the switch remains unknown.
6.2.5 References
1 Miller CD, El-Kholi R, Faragon JJ, Lodise TP. Prevalence and
risk factors for clinically significant drug interactions with
antiretroviral therapy. Pharmacotherapy 2007; 27:
1379–1386.
2 Shah S, Shah S, McGowan J et al. Identification of drug
interactions involving ART in New York City HIV specialty
clinics. 14th Conference on Retroviruses and Opportunistic
Infections. Los Angeles, CA. February 2007 [Abstract 573].
Antivir Ther 2010; 15: 413–423.
4 Evans-Jones JG, Cottle LE, Back DJ et al. Recognition of risk
for clinically significant drug interactions among
HIV-infected patients receiving antiretroviral therapy. Clin
Infect Dis 2010; 50: 1419–1421.
5 Kigen G, Kimaiyo S, Nyandiko W et al.; USAID-Academic
Model for Prevention Treatment of HIV/AIDS. Prevalence of
potential drug-drug interactions involving antiretroviral
drugs in a large Kenyan cohort. PLoS ONE 2011; 6:
e16800.
6 Patel N, Abdelsayed S, Veve M, Miller CD. Predictors of
clinically significant drug-drug interactions among patients
treated with nonnucleoside reverse transcriptase inhibitor-,
protease inhibitor-, and raltegravir-based antiretroviral
regimens. Ann Pharmacother 2011; 45: 317–324.
7 de Maat MM, Frankfort SV, Mathôt RA et al. Discrepancies
between medical and pharmacy records for patients on
anti-HIV drugs. Ann Pharmacother 2002; 36: 410–415.
8 Seden K, Mathew T, Bradley M et al. Patients accessing HIV
treatment via sexual health services: what are the risks of
the dual case-note system? Int J STD AIDS 2012; 23:
99–104.
9 Kredo T, Van der Walt JS, Siegfried N, Cohen K. Therapeutic
drug monitoring of antiretrovirals for people with HIV.
Cochrane Database Syst Rev 2009; (3): CD007268.
April 2012).
11 la Porte C, Back D, Blaschke T et al. Updated guideline to
perform therapeutic drug monitoring for antiretroviral
agents. Rev Antivir Ther 2006; 3: 4–14.
12 Fox Z, Phillips A, Cohen C et al. Viral suppression and
detection of drug resistance following interruption of a
suppressive non-nucleoside reverse transcriptase inhibitor
based regimen. AIDS 2008; 22: 2279–2289.
13 Taylor S, Boffito M, Khoo S et al. Stopping antiretroviral
therapy. AIDS 2007; 21: 1673–1682.
14 Taylor S, Jayasuriya A, Fisher M et al. Lopinavir/ritonavir
single agent therapy as a universal combination
antiretroviral stopping strategy: results from the STOP 1
and STOP 2 studies. J Antimicrob Chemother 2012; 67:
675–680.
15 Winston A, Pozniak A, Smith N et al. Dose escalation or
immediate full dose when switching from efavirenz to
nevirapine-based highly active antiretroviral therapy
in HIV-1-infected individuals? AIDS 2004; 18:
572–574.
16 Viramune Summary of Product Characteristics. UK,
Boehringher Ingelheim Ltd, 2011.
17 Kesselring AM, Wit FW, Sabin CA et al. Risk factors for
treatment limiting toxicities in patients starting nevirapine
containing antiretroviral therapy. AIDS 2009; 23:
1689–1699.
18 Waters L, Fisher M, Winston A et al. A phase IV,
double-blind, multicentre, randomized, placebo-controlled,
pilot study to assess the feasibility of switching individuals
receiving efavirenz with continuing central nervous system
adverse events to etravirine. AIDS 2011; 25: 65–71.
19 Crauwels H, Vingerhoets J, Ryan R et al. Pharmacokinetic
parameters of once-daily TMC278 following administration
of EFV in healthy volunteers. 18th Conference on
Retroviruses and Opportunistic Infections. Boston MA.
February 2011 [Abstract 630].
20 Maitland D, Boffito M, Back D et al. Therapeutic drug
monitoring (TDM) of atazanavir (ATV) during the first 4
weeks of therapy after switching from efavirenz (EFV)
containing regimen. 7th International Congress on Drug
Therapy in HIV Infection. Glasgow, UK. November 2004
[Abstract 293].
21 Iwamoto M, Wenning LA, Petry AS et al. Minimal effects of
ritonavir and efavirenz on the pharmacokinetics of
raltegravir. Antimicrob Agents Chemother 2008; 52:
4338–4343.
22 Waters L, Newell S, Else L et al. Pharmacokinetics (PK),
efficacy and safety of switching from efavirenz (EFV) to
maraviroc (MVC) twice-daily (BID) in patients suppressed on
an EFV-containing regimen as initial therapy. 13th
European AIDS Conference. Belgrade, Serbia. October 2011.
6.3 Switching antiretroviral therapy in virological
suppression
6.3.1 Introduction
In patients on fully virally suppressive regimens, switching
individual components of the ART combination regimen is
frequently considered for several reasons, including: management of ARV drug toxicity or intolerance, desire for
once-daily dosing and reduced pill burden, management of
potential DDIs, patient preference and cost [1]. Guidance
on the management of drug toxicity of individual ARVs is
not within the scope of these guidelines. Guidance on
interventions to support adherence, including once-daily
dosing and FDCs is addressed in Section 6.1 (Adherence)
and pharmacological considerations on switching ARVs is
discussed in Section 6.2.4 (Switching therapy: pharmacological considerations).
Switching individual components of an ART regimen
may well improve adherence and tolerability, but should
not be at the cost of virological efficacy. The following
guidance concerns the impact on virological efficacy of
either switching the third agent or the NRTI backbone in a
combination ART regimen or simplifying to boosted PI
monotherapy. Evidence from a systematic literature review
(Appendix 2) was evaluated as well as the impact on
critical treatment outcomes of the different switching
strategies assessed. Critical outcomes included virological
suppression at 48 weeks, virological failure and discontinuation from grade 3/4 events.
6.3.2 Switching antiretrovirals in combination
antiretroviral therapy
• We recommend, in patients on suppressive ART regimens, consideration is given to differences in side effect
profile, DDIs and drug resistance patterns before switching any ARV component (GPP).
• We recommend in patients with previous NRTI resistance
mutations, against switching a PI/r to either an NNRTI or
an INI as the third agent (1B).
Auditable measure. Number of patients with an
undetectable VL on current regimen and documented previous NRTI resistance who have switched a PI/r to either an
NNRTI or INI as the third agent.
6.3.2.2 Rationale
Within-class switches are usually undertaken to improve
ARV tolerability. The available evidence for current recommended third agents is limited but switching PI/r or NNRTIs
in virologically suppressed patients has, in a small number
of studies, not been associated with loss of virological
efficacy [2–4]. Consideration should, however, be given to
differences in side effect profiles, DDIs and food effect and
for switching between different PIs to the previous history of
major PI mutations, as this may potentially have an adverse
effect on the virological efficacy of the new PI/r.
For NRTIs, recent studies have mainly evaluated switching
from a thymidine analogue to either TDF or ABC to manage
patients with lipoatrophy or have investigated switching to
one of two available NRTI FDCs (TDF and FTC or ABC and
3TC). If screening for HLA-B*57:01 positivity is undertaken
before the switch to ABC, then similar virological efficacy is
seen in patients switched to ABC-3TC FDC compared with a
switch to TDF-FTC FDC [5]. In general, in the absence of
previous resistance mutations, switching within class should
result in maintaining virological suppression.
Several RCTs have assessed switching between classes
(PI to NNRTI and PI to INI) in patients who are virologically
suppressed. A meta-analysis of six trials showed noninferiority in maintenance of virological suppression when
switching from a PI (both ritonavir boosted and unboosted)
to NVP compared with continuing the PI but was associated with more discontinuations due to liver toxicity [6].
Previous treatment failure on an NRTI-containing regimen
has been associated with an increased risk of virological
failure when switching from a PI to an NNRTI-based
regimen [7]. A recent cohort analysis showed similar rates
of virological failure at 12 months in patients switching
from a first-line PI/r to either EFV or NVP compared with
continuing on the PI/r [8]. If switching to NVP, consideration should be given to the risk of hypersensitivity reactions and hepatotoxicity. Similar rates have been reported
in virologically suppressed compared with ART-naïve
patients stratified for CD4 cell count and gender [9,10]. For
patients without previous NRTI or NNRTI resistance mutations switching from a PI/r to any of the current licensed
NNRTIs is likely to maintain virological efficacy and choice
of NNRTI will depend on side effect profile, tolerability and
patient preference.
Switching from a PI/r to the INI, RAL, in virologically
suppressed patients has been evaluated in three RCTs. Two
studies have shown that previous history of NRTI resistance
mutations increases the risk of subsequent virological
failure on switching compared with continuing on a PI/r
[11,12]. This association was not seen in a third trial [13].
However, it is not surprising that switching from an ARV
with a high genetic barrier to one with a low genetic barrier
to resistance may potentially increase the risk of virological failure if the activity of the NRTI backbone has been
compromised by previous NRTI resistance.
There are limited data on switching from an NNRTI to an
alternative third agent in virologically suppressed patients;
however, consideration must be given to previous treatment history and potential pharmacokinetic interactions.
The latter is discussed in more detail in Section 6.2.4
(Switching therapy: pharmacological considerations).
6.3.2.3 References
1 Vo TT, Ledergerber B, Keiser O et al.; Swiss HIV Cohort
Study. Durability and outcome of initial antiretroviral
treatments received during 2000–2005 by patients in the
Swiss HIV Cohort Study. J Infect Dis 2008; 197: 1685–1694.
2 Mallolas J, Podzamczer D, Milinkovic A et al. Efficacy and
safety of switching from boosted lopinavir to boosted
atazanavir in patients with virological suppression receiving
a LPV/r-containing HAART: the ATAZIP study. J Acquir
Immune Defic Syndr 2009; 51: 29–36.
3 Soriano V, García-Gasco P, Vispo E et al. Efficacy and safety
of replacing lopinavir with atazanavir in HIV-infected
patients with undetectable plasma viraemia: final results of
the SLOAT trial. J Antimicrob Chemother 2008; 61: 200–205.
4 Waters L, Fisher M, Winston A et al. A phase IV,
double-blind, multicentre, randomized, placebo-controlled,
pilot study to assess the feasibility of switching individuals
receiving efavirenz with continuing central nervous system
adverse events to etravirine. AIDS 2011; 25: 65–71.
5 Martin A, Bloch M, Amin J et al. Simplification of
antiretroviral therapy with tenofovir-emtricitabine or
abacavir-lamivudine: a randomized, 96-week trial. Clin
Infect Dis 2009; 49: 1591–1601.
6 Ena J, Leach A, Nguyen P. Switching from suppressive
protease inhibitor-based regimens to nevirapine-based
regimens: a meta-analysis of randomized controlled trials.
HIV Med 2008; 9: 747–756.
7 Martinez E, Arnaiz JA, Podzamczer D et al. Substitution of
nevirapine, efavirenz or abacavir for protease inhibitors in
patients with human immunodeficiency virus infection.
N Engl J Med 2003; 349: 1036–1046.
8 Bommenel T, Launay O, Meynard JL et al. Comparative
effectiveness of continuing a virologically effective first-line
boosted protease inhibitor combination or of switching to a
three-drug regimen containing either efavirenz, nevirapine
or abacavir. J Antimicrob Chemother 2011; 66: 1869–1877.
9 Kesselring AM, Wit FW, Sabin CA et al. Risk factors for
treatment limiting toxicities in patients starting nevirapine
containing antiretroviral therapy. AIDS 2009; 23:
1689–1699.
10 Wit FW, Kesselring AM, Gras L et al. Discontinuation of
nevirapine because of hypersensitivity reactions in patients
with prior treatment experience, compared with
treatment-naive patients: the ATHENA cohort study. Clin
Infect Dis 2008; 46: 933–940.
11 Eron JJ, Young B, Cooper DA et al. Switch to a
raltegravir-based regimen versus continuation of a
lopinavir-ritonavir-based regimen in stable HIV-infected
patients with suppressed viraemia (SWITCHMRK 1 and 2):
two multicentre, double-blind, randomised controlled trials.
Lancet 2010; 375: 396–407.
12 Vispo E, Barreiro P, Maida I et al. Simplification from
protease inhibitors to once- or twice-daily raltegravir: the
ODIS trial. HIV Clin Trials 2010; 11: 197–204.
13 Martínez E, Larrousse M, Llibre JM et al. Substitution of
raltegravir for ritonavir-boosted protease inhibitors in
HIV-infected patients: the SPIRAL study. AIDS 2010; 24:
1697–1707.
6.3.3 Protease inhibitor monotherapy
• We recommend continuing standard combination ART
as the maintenance strategy in virologically suppressed
patients (1C). (There are insufficient data to recommend
PI/r monotherapy in this clinical situation.)
Auditable measure. Number of patients on PI/r
monotherapy as ART maintenance strategy in virologically
suppressed patients and record of rationale.
6.3.3.2 Rationale
For the assessment and evaluation of evidence, GRADE tables
were constructed (Appendix 3). Virological suppression, drug
resistance and serious adverse events were defined as critical
outcomes. From the systematic literature review (Appendix 2)
10 RCTs were identified, investigating the use of either LPV/r
or DRV/r in stable, virologically suppressed patients without
active hepatitis B coinfection [1–13].
Assessment of virological suppression showed significantly fewer patients on PI monotherapy maintaining virological suppression compared with those continuing on
standard combination ART (RR 0.95, 95% CI 0.9, 0.99),
although the difference was small. A similar result has
previously been reported in a meta-analysis [14]. VL
rebound is usually at low level, and is easily reversed by
reintroduction of NRTIs. The long-term consequences of
this viral rebound and re-suppression are unknown. There
were no differences in the frequency of emergence of viral
resistance, or of serious adverse events, although few
patients developed drug resistance and thus confidence in
the estimate of this effect is low. One potential concern is
the development of CNS disease in patients on PI monotherapy [6,11]; however, we did not identify a difference in
this outcome although the quality of the evidence is low.
Further data are required.
Overall, there is no significant clinical benefit of PI monotherapy compared with standard combination ART, which
might offset the disadvantage of a lower rate of viral suppression with PI monotherapy. For this reason PI monotherapy
should not be used in unselected patient populations for
maintaining virological suppression where standard ART is an
acceptable alternative. There may be potential benefits of PI
monotherapy, in terms of drug resistance, long-term drug
toxicity and cost [15] but further data are required. The
ongoing ‘Protease Inhibitor monotherapy vs. Ongoing Triple
therapy in the long-term management of HIV infection’
(PIVOT) trial has been designed to address these issues [16].
The primary endpoint is drug resistance.
We recognize that PI monotherapy may well be an
acceptable option in some specific patient populations but
there are few data to provide recommendations. Clinicians
might consider PI monotherapy in patients who are unable
to tolerate NRTIs due to toxicities or as a short-term
measure to manage or bridge complex clinical scenarios
(e.g. stopping certain NNRTI-containing regimens or managing toxicity overdose or acute illness). Where PI monotherapy is considered, DRV/r (dosed once or twice daily) or
LPV/r (dosed twice daily) should be used. ATV/r mono-
therapy is not recommended as it has been associated with
higher rates of virological failure [17,18]. PI monotherapy
is not recommended in patients with active hepatitis B
coinfection.
6.3.3.3 References
1 Arribas JR, Pulido F, Delgado R et al. Lopinavir/r as single
drug therapy for maintenance of HIV-1 viral suppression.
48-week results of a randomised controlled open label proof
of concept pilot clinical trial (OK study). J Acquir Immune
Defic Syndr 2005; 40: 280–287.
2 Pulido F, Arribas JR, Delgado R et al. Lopinavir-ritonavir
monotherapy versus lopinavir-ritonavir and two nucleosides
for maintenance therapy of HIV. AIDS 2008; 22: F1–F9.
3 Arribas JR, Delgado R, Arranz A et al. Lopinavir-ritonavir
monotherapy versus lopinavir-ritonavir and 2 nucleosides
for maintenance therapy of HIV: 96-week analysis. J Acquir
4 Arribas JR, Horban A, Gerstoft J et al. The MONET trial:
darunavir/ritonavir with or without nucleoside analogues,
for patients with HIV RNA below 50 copies/ml. AIDS 2010;
24: 223–230.
5 Clumeck N, Rieger A, Banhegyi D et al. 96 week results
from the MONET trial: a randomized comparison of
darunavir/ritonavir with versus without nucleoside
analogues, for patients with HIV RNA <50 copies/mL at
baseline. J Antimicrob Chemother 2011; 66: 1878–1885.
6 Winston A, Fätkenheuer G, Arribas J et al. Neuropsychiatric
adverse events with ritonavir-boosted darunavir
monotherapy in HIV-infected individuals: a randomised
prospective study. HIV Clin Trials 2010; 11: 163–169.
7 Cahn P, Montaner J, Junod P et al. Pilot, randomized study
assessing safety, tolerability and efficacy of simplified LPV/r
maintenance therapy in HIV patients on the 1 PI-based
regimen. PLoS ONE 2011; 6: e23726.
8 Katlama C, Valantin MA, Algarte-Genin M et al. Efficacy of
darunavir/ritonavir maintenance monotherapy in patients
with HIV-1 viral suppression: a randomized open-label,
noninferiority trial, MONOI-ANRS 136. AIDS 2010; 24:
2365–2374.
9 Meynard JL, Bouteloup V, Landman R et al. Lopinavir/
ritonavir monotherapy versus current treatment continuation
for maintenance therapy of HIV-1 infection: the KALESOLO
trial. J Antimicrob Chemother 2010; 65: 2436–2444.
10 Nunes EP, Santini de Oliveira M, Merçon M et al.
Monotherapy with lopinavir/ritonavir as maintenance after
HIV-1 viral suppression: results of a 96-week randomized,
controlled, open-label, pilot trial (KalMo study). HIV Clin
Trials 2009; 10: 368–374.
11 Gutmann C, Cusini A, Günthard HF et al. Randomized
controlled study demonstrating failure of LPV/r
monotherapy in HIV: the role of compartment and
CD4-nadir. AIDS 2010; 24: 2347–2354.
12 Hasson H, Galli L, Gallotta G et al. HAART simplification
with lopinavir/ritonavir monotherapy in HIV/HCV coinfected
patients starting anti-HCV treatment: final results of a
randomised, proof-of-principle clinical trial (KAMON 2
Study). 6th IAS Conference on HIV Pathogenesis, Treatment
and Prevention. Rome, Italy. July 2011 [Abstract: CDB358].
13 Waters L, Jackson A, Singh K et al. The impact of continued
HAART versus lopinavir/ritonavir monotherapy (mLPV/r) on
body fat and bone mineral density (BMD) as measured by
DEXA: 48 week results of a randomised study. XVII
International AIDS Conference. Mexico City, Mexico. August
2008 [Abstract CDB0193].
14 Mathis S, Khanlari B, Pulido F et al. Effectiveness of
protease inhibitor monotherapy versus combination
antiretroviral maintenance therapy: a meta-analysis. PLoS
ONE 2011; 6: e22003.
15 Gazzard B, Hill A, Anceau A. Cost-efficacy analysis of the
MONET trial using UK antiretroviral drug prices. Appl
Health Econ Health Policy 2011; 9: 217–223.
16 United Kingdom Medical Research Council. A randomised
controlled trial of a strategy of switching to boosted PI
monotherapy versus continuing combination ART for the
long-term management of HIV-1 infected patients who have
achieved sustained virological suppression on HAART
(PIVOT). Available at http://clinicaltrials.gov/ct2/show/
NCT01230580 (accessed May 2012).
17 Karlström O, Josephson F, Sönnerborg A. Early virological
rebound in a pilot trial of ritonavir boosted atazanavir as
maintenance monotherapy. J Acquir Immune Defic Syndr
2007; 44: 417–422.
18 Vernazza P, Daneel S. Schiffer V et al. Risk of CNS
compartment failure on PI monotherapy (ATARITMO study).
XVI International AIDS Conference. Toronto, Canada. August
2006 [Abstract WEPE0073].
6.4 Stopping therapy
• We recommend against treatment interruption or intermittent therapy in patients stable on a virally suppressive ART regimen (1A).
Proportion of patients with a CD4 cell count <350 cells/mL
not on ART.
6.4.2 Rationale
Several RCTs have investigated the efficacy of CD4 cell
count-guided intermittent therapy as a potential strategy
to reduce long-term risk of drug toxicity and drug resistance [1–4]. In the largest of these, patients were randomly
allocated to either CD4 cell count-guided intermittent
therapy (stopping ART once CD4 cell count >350 cells/mL,
restarting when CD4 cell count falls to 250 cells/mL) compared with a continuous ART [1]. The trial showed intermittent therapy was associated with a significantly higher
rate of opportunistic disease and all-cause mortality and
a higher rate of major cardiovascular, renal or hepatic
disease. The effect was seen at all CD4 cell count levels.
The study showed for the first time that continuous ART
with virological suppression is associated with a reduction
in the risk of non-AIDS co-morbidities and all-cause mortality as well as HIV disease progression. For this reason,
treatment interruption or intermittent therapy is not recommended.
Once ART has been started in a patient with HIV infection, it should be continued. Temporary interruptions of
1–2 days can usually be managed and are unlikely to be
associated with adverse outcomes. Longer interruptions of
ART should only be considered in exceptional circumstances. These may include:
• After pregnancy, in women who have taken ART during
pregnancy to prevent mother-to-child transmission, but
do not otherwise require treatment.
• After early initiation of ART (CD4 cell counts >500
cells/mL) (e.g. when started to reduce infectiousness).
• Severe drug toxicity (e.g. hepatotoxicity).
• Severe psychological distress.
Guidance on pharmacokinetic considerations when stopping ART is contained in Section 6.2.3 Stopping therapy:
pharmacological considerations.
6.4.3 References
1 El-Sadr WM, Lundgren JD, Neaton JD et al. CD4+
count-guided interruption of antiretroviral treatment. N Engl
J Med 2006; 355: 2283–2296.
2 Danel C, Moh R, Minga A et al. CD4-guided structured
antiretroviral treatment interruption strategy in HIV-infected
adults in west Africa (Trivacan ANRS 1269 trial): a
randomised trial. Lancet 2006; 367: 1981–1989.
3 Cardiello PG, Hassink E, Ananworanich J et al. A prospective,
randomized trial of structured treatment interruption for
patients with chronic HIV type 1 infection. Clin Infect Dis
2005; 40: 594–600.
4 Ananworanich J, Gayet-Ageron A, Le Braz M et al.
CD4-guided scheduled treatment interruptions compared with
continuous therapy for patients infected with HIV-1: results
of the Staccato randomised trial. Lancet 2006; 368: 459–465.
7.0 Managing virological failure
7.1 Introduction
For detailed guidance on HIV VL, resistance and genotropism testing, the reader should consult BHIVA guidelines
for the routine investigation and monitoring of adult HIV1-infected individuals 2011 [1] (http://www.bhiva.org/
Monitoring.aspx).
The following recommendations concern the management of patients experiencing virological failure on ART.
Patient populations at the time of virological failure will
include those with no or limited HIV drug resistance
through to those with three-class failure and either no or
limited treatment options. For the assessment and evaluation of evidence, priority questions were agreed and
outcomes were ranked (critical, important and not important) by members of the Writing Group. For patients with
no or limited HIV drug resistance the following were
ranked as critical outcomes: viral suppression <50
copies/mL at 48 weeks, development of resistance, discontinuation rates for clinical and laboratory adverse
events. For patients with three-class failure/few therapeutic options: clinical progression, median CD4 cell
count change at 48 weeks, and development of new
resistance. Treatments were compared where data were
available and differences in outcomes assessed. Details of
the search strategy and literature review are contained in
Appendix 2.
In the UK, the virological failure rate on current first-line
regimens in 2008–2009 was approximately 10% at 1 year
[2]. The options for switch depend on the most recent and
past ARV treatments as well as current and archived resistance results. As genotypic testing in ARV-naïve patients is
now performed routinely and is recommended practice,
detection of resistance at virological failure is rarely a
result of transmitted drug resistance and failure to adapt
first-line treatment [3,4].
The general principles for the management of patients
experiencing virological failure are outlined in Boxes 7.1
and 7.2 as GPPs. Details of typical patterns of HIV drug
resistance found in patients with a history of or presenting
with virological failure are outlined in Box 7.3. For guidance on HIV VL, drug resistance and tropism testing, the
reader should consult the BHIVA routine investigation and
monitoring guidelines [1].
• Record in patient’s notes of resistance result at ART
initiation (if available) and at first VL >400 copies/mL
and/or before switch.
• Record in patient’s notes of adherence assessment and
tolerability/toxicity to ART in patients experiencing
virological failure or repeated viral blips.
• Number of patients experiencing virological failure on
current ART regimen.
• Proportion of patients experiencing virological failure
switched to a new suppressive regimen within 6
months.
• Proportion of patients on ART with previously documented HIV drug resistance with VL <50 copies/mL.
• Record of patients with three-class virological failure
with or without three-class resistance referred/
discussed in multidisciplinary team with expert advice.
7.2 Blips, low-level viraemia and
virological failure
In patients on ART:
• A single VL 50–400 copies/mL preceded and followed by
an undetectable VL is usually not a cause for clinical
concern (GPP).
• We recommend a single VL >400 copies/mL is investigated further, as it is indicative of virological failure
(1C).
• We recommend in the context of repeated viral blips,
resistance testing is attempted (1D).
7.2.2 Rationale
7.2.2.1 Blips
Optimal HIV control is ordinarily reflected by complete
viral suppression with an undetectable VL. A virological
blip is variably defined but for the purposes of these
guidelines the definition that has been adopted is a
detectable VL <400 copies/mL, which is preceded and followed by an undetectable result without any change of
therapy. Blips are frequent and represent random variation around a mean undetectable VL [5–7]. Many patients
have at least one at some time [8] when they are not
predictive of virological failure or associated with emergent resistance in most studies [5,9,10]. VL assay variation and laboratory processing artefacts account for
many blips (i.e. no ‘true’ increase in viral replication),
which partly explains why blips do not appear to compromise long-term outcomes [9,11–13]. However, those
with sustained low-level increases in VL run a higher risk
of virological failure. Most blips are low level [median
magnitude 79 copies/mL in one study (range 51–201)]
and short lived [median 2.5 days (range 2–11.5)] [7]. In a
retrospective study, 28.6% of patients, experienced VL
increases from 50 to 500 copies/mL over 8 years; 71% of
these were blips [8].
Review and reiteration of the importance of full adherence, as well as looking for any tolerability/toxicity
issues, DDIs/food interactions, and archived resistance
should take place. However, blips do not appear to be
related to intercurrent illness, vaccination, baseline CD4
cell count/VL, duration of preceding suppression or level
of adherence [7,14,15]. Therefore, it is the recommendation of the Writing Group that a VL result of 50–400
copies/mL preceded and followed by an undetectable VL
should not be a cause of clinical concern. In the context
of repeated blips, it may then be useful to test for resistance [16,17].
7.2.2.2 Low-level viraemia
Low-level viraemia (LLV) is defined as a repeatedly
detectable but low level of viraemia over a sustained
period of time. For the purposes of these guidelines, <400
copies/mL is used although it is recognized that some
patients have VLs up to 1000 copies/mL without development of resistance and with therapeutic drug levels.
LLV is observed in up to 8% of individuals [18] and is
associated with an increased risk of virological rebound
(>400 copies/mL) [6,19]. The likelihood of resuppression
after LLV is greater for lower magnitudes of viraemia:
41% after two consecutive VLs >50 copies/mL compared
with 12% after two VLs >200 copies/mL [20]. LLV is
associated with resistance (37% in one study [21]) that
may be associated with LLV magnitude; in one analysis,
maximum VL was higher in those with who developed
resistance (368 vs. 143 copies/mL; P=0.008). LLV is also
associated with immune activation [10]. Low-level antigenic exposure differentially affects T-cell activation and
HIV-specific T-cell response. In cohort studies [19] and
clinical trials [21], patients on PI/r-based ART are more
likely to experience detectable viraemia than those on
NNRTI. In the absence of clear data, the Writing Group
believes LLV on a low-genetic barrier regimen warrants
prompt regimen change. This is especially true where
ART combination without a boosted PI is being used
[22,23]. Further evaluation should follow as for that set
out in Box 7.1.
7.2.2.3 Virological failure
Failure is defined as ‘failure to achieve a VL <50 copies/mL
6 months after commencing ART or following viral suppression to <50 copies/mL a VL rebound to >400 copies/mL
on two consecutive occasions’. In the UK, approximately
18% of those achieving an undetectable VL in 2008–2009
experienced VL rebound. In the same database, among
drug-experienced patients the overall prevalence of resistance was 44% in 2007 [1]]. Confirmation of virological
failure at any stage should lead to the practice set out in
Box 7.1.
Box 7.1 Best practice for the management of patients
with virological failure
• Factors affecting adherence and drug exposure,
including tolerability/toxicity issues, DDIs/food
interactions, ARV potency, significant renal/liver
disease and mental health/drug dependency problems are evaluated.
• Resistance testing is performed while on failing
therapy or within 4 weeks of discontinuation.
• Past ART and resistance tests are reviewed for
archived mutations.
• Tropism testing is performed if MVC is being considered.
• Intensification with an additional active ARV is not
recommended.
• Once virological failure is confirmed and a resistance
result available, the regimen is changed as soon as
possible to avoid accumulation of resistance
mutations.
The choice of the new ART regimen will primarily
depend on the results of resistance testing and the
patient’s preference. Additional considerations include
the results of tropism and HLA-B*57 testing, DDIs/food
interactions, co-morbidities and future therapy options.
The goal of the new combination is to re-establish a VL
<50 copies/mL.
Box 7.2 Best practice for the management of patients
with three-class virological failure
• In patients with ongoing viraemia and with few
options to construct a fully suppressive regimen,
referral for specialist advice and/or discussion in a
multidisciplinary team ‘virtual’ clinic.
• Include at least two and preferably three fully active
agents with at least one active PI/r (e.g. DRV/r) and
one agent with a novel mechanism of action (CCR5
antagonist/integrase or fusion inhibitor).
• Treatment interruption is not recommended.
Box 7.3 Typical resistance patterns on virological failure
• No resistance (WT virus).
• 3TC/FTC resistance (M184V/I) following any firstline therapy, including TDF/FTC or ABC/3TC.
• NNRTI resistance (e.g. K103N or Y181C/I/V) and/or
3TC/FTC resistance (following first-line therapy with
NNRTI-based regimen, including TDF/FTC or ABC/
3TC).
• INI resistance (e.g. Q148 or N155H) and/or 3TC/FTC
resistance (following first-line therapy with RALbased regimen, including TDF/FTC or ABC/3TC).
• Extended RT resistance (e.g. K65R/L74V or thymidine
analogue mutations) (following suboptimal regimens/
patients with more extensive drug history associated
with virological failure).
• Three-class resistance (indicating NRTI, NNRTI and PI)
(following multiple failing regimens).
• Limited or no therapeutic options (following multiple
failing regimens, including the newer drugs with
novel actions).
7.3 Patients with no or limited
drug resistance
• We recommend patients experiencing virological failure
on first-line ART with WT virus at baseline and without
emergent resistance mutations at failure switch to a
PI/r-based combination ART regimen (1C).
• We recommend patients experiencing virological failure
on first-line ART with WT virus at baseline and limited
emergent resistance mutations (including two-class
NRTI/NNRTI) at failure switch to a new PI/r-based
regimen with the addition of at least one, preferably two,
active drugs (1C).
• We recommend patients experiencing virological
failure on first-line PI/r plus two-NRTI-based regimens,
with major protease mutations, switch to a new active
PI/r with the addition of at least one, preferably two,
active agents of which one has a novel mechanism of
action (1C).
• We recommend against switching a PI/r to an INI or
NNRTI as the third agent in patients with historical or
existing RT mutations associated with NRTI resistance
or past virological failure on NRTIs (1B).
7.3.2 Rationale
7.3.2.1 First-line treatment failure with no resistance
A significant minority of patients have WT virus despite
failing on therapy [24–30]. Failure here is usually attributable to poor treatment adherence with drug levels that
are both insufficient to maintain VL suppression and inadequate to select out viral mutations associated with drug
resistance detectable on standard tests. Factors affecting
adherence such as tolerability/toxicity issues, regimen convenience, drug–food interactions and mental health/drug
dependency problems should be fully evaluated and where
possible corrected before initiation of the new regimen.
Additional adherence support should be considered and
careful discussion with the patient take place. TDM may be
of benefit in individual patients in confirming low/absent
therapeutic drug levels and enabling discussion with the
patient.
A priority question the Writing Group addressed was
whether patients failing an NNRTI-based ART without
detectable resistance should receive a PI/r-based regimen.
The absence of detectable resistance mutations does not
exclude the presence of mutations in minor virus populations, especially with the NNRTIs [9–11]. This may lead to
subsequent failure if the same first-line drugs, or drugs in
the same class, are prescribed [31,32]. Testing for minority
resistance is a specialist test and expert interpretation by a
virologist is essential. There is no indication for routine
minority species testing in patients failing with WT virus
on therapy.
The recommendation of the Writing Group is that, following NNRTI/two NRTIs virological failure when no
resistance mutations exist, a switch to a PI/r-based
regimen should lead to virological suppression and is
unlikely to lead to emergent resistance. The decision
as to whether to restart the same NNRTI-based combination or switch to another NNRTI, RAL or MVC (where
CCR5 tropism has been confirmed) has to be individualized to the patient, their history of virological failure,
and to whether further switches in the combination are
occurring.
No supportive data exist for management of virological
failure when this has developed on first-line therapy with
RAL/two NRTIs but the general principles set out for
NNRTI-based failure would still apply. However, the high
genetic barrier of PI/r reduces the risk of low-level resistance developing.
7.3.2.2 First-line treatment failure with non-nucleoside
reverse transcriptase inhibitor resistance
Up to two-thirds of virologically failing patients harbour
viruses with NNRTI and half NRTI mutations at 48 weeks
[27–30,33]: with increasing time, there will be accumulation of resistance mutations that may compromise
second-line regimens [34]. Although potential options for
second-line therapy after failure on an NNRTI-containing
regimen include RAL, ETV and MVC as the third agent
(RPV is not licensed for this indication), evidence supports the use of a PI/r. A switch to any PI/r-based
regimen should lead to virological suppression and is
unlikely to lead to further emergent resistance and should
be considered whenever possible. Where NRTI resistance
has been documented or likely, these should be replaced
and new active NRTIs or other ARVs should be incorporated. There are no direct comparisons of the boosted PIs
in second-line treatment after first-line failure on an
NNRTI-based regimen and choice would be individualized
to the patient. Sequencing from an EFV or NVP-based
regimen to ETV is not recommended [35] although it
remains an option when switched as part of a new combination when only K103N is present. Switching to RAL
or MVC with two active NRTIs is an option but is also
not recommended in a patient with historical or existing
RT mutations/previous NRTI virological failure [36].
7.3.2.3 First-line treatment failure on a
ritonavir-boosted protease inhibitor-based two nucleoside
reverse transcriptase inhibitor regimen with or without
protease inhibitor resistance
Less than 1% of patients harbour viruses with primary PI
mutations and 10–20% NRTI mutations at 48 weeks, with
75% having WT virus [24,27–29,37,38]. There are currently
limited data regarding the efficacy of switching to another
PI/r, NNRTI, MVC or RAL-based regimen and again the
decision is individualized to the patient. However, switching to RAL, MVC or NNRTI in a patient with historical or
existing RT mutations is not recommended because of an
increased risk of virological failure and further emergence
of resistance [36]. By contrast, because of the high genetic
barrier of PI/r, sequencing to a regimen that includes a new
PI/r is unlikely to lead to further emergent resistance and is
recommended. Where PI/r mutations exist, DRV/r is the
preferred agent unless resistance is likely.
7.3.2.4 First-line treatment failure with integrase
inhibitor-based resistance
Up to one-half of patients harbour viruses with primary
integrase mutations and 25% NRTI mutations at 48 weeks:
approximately half have WT virus [26,33,37,39]. Again,
there are no data supporting a switch to PI/r, NNRTI or
MVC but sequencing to a new regimen that includes PI/r is
unlikely to lead to further emergent resistance and is recommended. Switching to NNRTI or MVC with two active
NRTIs is an option but is also not recommended in a
patient with historical or existing RT mutations/previous
NRTI virological failure. Patients experiencing virological
failure on RAL should switch to a new regimen as soon as
possible to reduce the risk of accumulating resistance
mutations that may affect susceptibility to newer INIs such
as dolutegravir.
7.4 Patients with triple-class (non-nucleoside reverse
transcriptase inhibitor, nucleoside reverse transcriptase
inhibitor, protease inhibitor) virological failure with or
without triple-class resistance
• We recommend patients with persistent viraemia and
with limited options to construct a fully suppressive
regimen are discussed/referred for expert advice (or
through virtual clinic referral) (GPP).
• We recommend patients with triple-class resistance
switch to a new ART regimen containing at least two
and preferably three fully active agents with at least one
active PI/r such as DRV/r or TPV/r and one agent with
a novel mechanism (CCR5 receptor antagonist or
integrase/fusion inhibitor) with ETV an option based on
viral susceptibility (1C).
7.4.2 Rationale
Risk of development of triple-class virological failure is
relatively low at about 9% at 9 years from start of ART
[40]. Until the last few years, limited treatment options
have been available for people with HIV who have had
virological failure with the three original classes of HIV
ARV drugs (triple-class virological failure) of whom many
have developed triple-class resistance. Most of these
patients have received suboptimal ARV treatment, often
from the pre-HAART era, or have adhered poorly to multiple regimens and have accumulated resistance. However,
with the introduction of several new agents active
against resistant virus, many of which have novel sites of
action, the potential for virological control akin to that
achieved with naïve patients has now become a probability [41,42].
Consequent to more active ARVs and improved strategies of management, there has been substantial improvement in the proportion of people who had virological
response after triple-class virological failure between 2000
and 2009 [43]. However, despite improvements in treatments, VLs cannot be suppressed for some people. In most
patients, this is a result of poor adherence but some
patients do have extended drug resistance and minimal
treatment options and achieving viral suppression is not
possible.
The drugs now most commonly used in triple-class
failure are boosted PIs, DRV/r and TPV/r, the INIs RAL
and elvitegravir (ELV), the CCR5 chemokine receptor
antagonist MVC, the NNRTI ETV, and the fusion inhibitor
enfuvirtide. The available data for DRV/r, TPV/r, RAL,
ELV, ETV and enfuvirtide show that they are most effective when used with other active drugs to which the virus
is susceptible based on resistance testing and antiviral
experience [44–52]. When used as the only effective
agent, the likelihood of achieving virological suppression
is significantly reduced and the development of emergent
resistance to the drug greater, and a future opportunity
for constructing an effective regimen is often lost.
A priority question the Writing Group addressed was
whether two or three fully active drugs should be
included in the new regimen. In a meta-analysis of 10
trials of patient with triple-class virological failure and
virological resistance where the study drug was added
to optimized background therapy and compared with
placebo, associations were demonstrated with increased
virological suppression (pooled OR 2.97) and larger CD4
cell count increases for the active agent [53]. Optimized
background therapy genotypic sensitivity scores (GSSs)
were also associated with larger differences in virological
suppression (P < 0.001 for GSS = 0, ⱕ1 and ⱕ2) and
CD4 cell count increase (GSS = 0, P < 0.001; GSS ⱕ 1,
P < 0.002; GSS ⱕ 2, P = 0.015) between the two groups.
In a further non-inferiority study, ELV was found to be
non-inferior to RAL when accompanied by a boosted PI
and a third agent [45].
This supports the use of at least two and possibly three
of these agents in the new regimen and with this strategy,
the goal of an undetectable VL is now achievable even in
most patients with multi-regimen failure. A priority question addressed in this group was whether regimens with
at least three fully active drugs should include NRTIs.
The recommendation from the Writing Group is that in
constructing an optimized background, continuing/
commencing NRTIs may contribute partial ARV activity to
a regimen, despite drug resistance [55,56].
For those drugs with a novel mode of action (integrase
and fusion inhibitors, and CCR5 antagonists), the absence
of previous exposure indicates susceptibility although
MVC is only active against patients harbouring CCR5
tropic virus. For DRV, TPV and ETV, the number and type
of mutations inform the degree to which these drugs are
active [56–58]. The potential for DDIs is also important.
ETV can be paired with DRV/r (but not TPV/r) and MVC
dosing is variable depending on the other drugs in the
new regimen; however, RAL and enfuvirtide require no
alteration.
Some patients can have a successfully suppressive fully
active three-drug regimen constructed without a PI/r [59].
Nevertheless, where feasible, a PI/r such as DRV/r should
be included because of its protective effect on emergent
resistance to the other drugs in the regimen although this
can be given DRV/r 800 mg/100 mg once daily in
treatment-experienced patients without DRV resistance
associated mutations [60]. Enfuvirtide is an option in
some patients despite the inconvenience of subcutaneous
injection and injection site reactions. With the availability of the newer agents, dual PI/r are not recommended
[61].
The same principles regarding reviewing adherence,
tolerability/toxicity issues, DDIs/food interactions, and
mental health/drug dependency problems apply. Additional adherence support is important in these patients as
the reason triple-class failure has occurred often relates
to past poor adherence. Additionally, the pill burden is
increased and careful discussion with the patient should
take place.
7.5 Patients with limited or no therapeutic options
when a fully viral suppressive regimen cannot be
constructed
• We recommend accessing newer agents through research
trials, expanded access and named patient programmes
(GPP).
• We suggest continuing/commencing NRTIs as this may
contribute partial ARV activity to a regimen, despite
drug resistance (2C).
• We recommend the use of 3TC or FTC to maintain a
mutation at codon position 184 of the RT gene (1B).
• We recommend against discontinuing or interrupting
ART (1B).
• We recommend against adding a single, fully active ARV
because of the risk of further resistance (1D).
• We recommend against the use of MVC to increase the
CD4 cell count in the absence of CCR5 tropic virus (1C).
7.5.2 Rationale
This situation usually occurs following attempts in
patients with triple-class failure to achieve virological
suppression with the newer agents and often indicates
adherence issues have not been addressed successfully or
sequential addition of the newer agents has occurred
without incomplete viral suppression and selection of
resistance to the new drug.
There is evidence from cohort studies that continuing
therapy, even in the presence of viraemia and the absence
of CD4 T-cell count increases, reduces the risk of disease
progression [62,63] whereas interruption may lead to a
rapid fall in CD4 cell count and a rise in VL [64,65]. Other
studies suggest continued immunological and clinical benefits if the HIV RNA level is maintained <10 000–20 000
copies/mL [66]. Continuing or commencing NRTIs, even in
the presence of known resistance may contribute partial
ARV activity [54,55]. Hence, if the CD4 cell count is well
maintained (>200 cells/mL), it may be better to continue the
failing regimen and not change treatment until investigational agents are available that can be put together with
drugs, which may have only partial activity at best, to
increase the likelihood of constructing virologically suppressive and durable regimen options.
In general, adding a single, fully active ARV to a
failing regimen is not recommended because of the risk
of rapid development of resistance. However, in patients
with a high likelihood of clinical progression (e.g. CD4
cell count <100 cells/mL) and limited drug options,
adding a single drug may reduce the risk of immediate
clinical progression, because even transient decreases in
HIV RNA and/or transient increases in CD4 cell counts
have been associated with clinical benefits [67]. Potential
benefits must be balanced with the ongoing risk of accumulating additional resistance mutations and patients
should maintain that regimen for the shortest period possible [68,69].
Where feasible, patients should be given the opportunity
to enrol in research studies or expanded access programmes evaluating investigational new drugs. Some
drugs are likely to be available in the near future that might
be sequenced in the same class (e.g. dolutegravir) although
others with novel sites of action (e.g. maturation inhibitors,
CD4 receptor antagonists, etc.) are still in earlier phases of
development and some years off randomized trials. Drugs
developed for, and used in, other settings such as pegylated
interferon that have been incidentally demonstrated to
decrease VL should not be used without discussion with an
experienced HIV physician as data are either too limited or
contradictory.
Several studies and an early meta-analysis suggested
that CCR5 receptor antagonists were associated with significant gains in CD4 cell counts even in the presence of
C-X-C chemokine receptor type 4 tropic virus. However, a
more recent meta-analysis refuted this finding (P=0.22)
when comparing with other new drugs [53].
A priority question that the Writing Group addressed was
whether 3TC/FTC should be used in maintaining an RT
mutation at codon 184 in patients with limited or no
therapeutic options.
Although the M184V mutation is associated with
resistance to 3TC/FTC, the mutation has a broad influence
on the RT enzyme. In vitro studies have shown that
M184V-possessing enzymes have lower processivity and
higher fidelity and replicate more slowly than WT
enzymes [70]. These observations have led to the hypothesis that maintaining this mutation using 3TC/FTC would
provide clinical benefit through the replication deficit
provided by the M184V mutation combined with the
residual antiviral activity of 3TC/FTC [71,72]. It has been
shown that patients harbouring M184V due to 3TC
failure who continue on 3TC monotherapy maintain
lower VLs than at baseline and rarely develop new RT or
protease mutations [73]. Moreover, ceasing 3TC monotherapy has been demonstrated to result in replication
capacity recovery and a reduction in CD4/CD8 ratio
driven by the de-selection of the M184V mutation [74].
This strategy is supported by the E-184 study which was
a small but randomized, open-label study of 3TC monotherapy vs. no therapy in patients failing ART [75].
Monotherapy was associated with significant smaller
increases in VL, smaller declines in CD4 cell counts, and
no selection of additional RT mutations.
Finally, the presence of M184V mutation enhances in
vitro susceptibility to TDF and this translated into a significant HIV RNA response in clinical trials of TDF intensification [76,77].
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8.0 Antiretroviral therapy in specific populations
For some patient populations, specific considerations need
to be taken into account when deciding when to start and
the choice of ART. The following sections outline specific
recommendations and the supporting rationale for defined
patient populations. In parallel to guidelines on ART in
adults, BHIVA also publishes guidelines on the management and treatment of specific patient populations, including coinfection with TB, coinfection with viral hepatitis B
or C, and HIV-positive pregnant women. An outline of the
recommendations for when to start and choice of ART,
from the BHIVA guidelines for TB and viral hepatitis is
summarized below. The reader should refer to the full,
published guidelines for these patient populations for more
detailed information and guidance on the BHIVA website
(http://www.bhiva.org/publishedandapproved.aspx) and be
aware that BHIVA clinical practice guidelines are periodically updated.
For these current guidelines, new guidance on when to
start and choice of ART has been developed for HIV-related
cancers, HIV-associated NC impairment, CKD, CVD and
women. The guidance only considers specific issues concerning the initiation and choice of ART in these patient
populations. Guidance on the management of pregnancy in
HIV-positive women has not been included.
8.1 HIV with tuberculosis coinfection
This guidance provides a brief summary of the key statements and recommendations regarding prescribing ART in
HIV-positive patients co-infected with TB. It is based on the
BHIVA guidelines for the treatment of TB/HIV coinfection
2011 [1], which should be consulted for further information. The full version of the guidelines is available on the
BHIVA website (http://www.bhiva.org/TB-HIV2011.aspx).
Timing of initiation of ART during TB therapy:
CD4 cell count
(cells/mL)
<100
100–350
>350
When to start HAART
Grade
As soon as practical within 2 weeks after starting
TB therapy
As soon as practical, but can wait until after
completing 2 months TB treatment, especially
when there are difficulties with drug
interactions, adherence and toxicities
At physician’s discretion
1B
Auditable measure. Proportion of patients with TB
and CD4 cell count <100 cells/mL started on ART within 2
weeks of starting TB therapy.
8.1.1.2 Rationale
Most patients with TB in the UK present with a low CD4 cell
count, often <100 cells/mL. In such patients, ART improves
survival, but can be complicated by IRD and drug toxicity.
Data suggest that ART can be delayed until the first 2
months of TB therapy has been completed but at CD4 cell
counts <50 cells/mL the short-term risk of developing
further AIDS-defining events and death is high, and ART
should be started as soon as practicable and within 2 weeks
of initiation of TB therapy [2–5]. Starting ART early in
severely immunosuppressed HIV-positive patients presenting with TB is associated with decreased mortality and a
lowering of the rates of disease progression but rates of IRD
are high.
Patients with HIV and a CD4 cell count >350 cells/mL
have a low risk of HIV disease progression or death during
the subsequent 6 months of TB treatment, depending on
age and VL [6]. They should have their CD4 cell count
monitored regularly and ART can be withheld during the
short-course of TB treatment.
One study performed in HIV-associated TB meningitis in
the developing world, where 90% of the patients were male,
the majority drug users, many with advanced disease and
the diagnosis being made clinically, showed no difference in
mortality starting ART early or late [7].
8.1.2 What to start
We recommend EFV in combination with TDF and FTC as first-line ART
in TB/HIV coinfection
We recommend that when rifampicin is used with EFV in patients over
60 kg, the EFV dose is increased to 800 mg daily. Standard doses of
EFV are recommended if the patient weighs <60 kg
We recommend that rifampicin is not used with either NVP or PI/r
We recommend that where effective ART necessitates the use of PI/r,
that rifabutin is used instead of rifampicin
1B
1C
1C
1C
Auditable measure. Proportion of patients with
active TB on anti-TB therapy started on ART containing
EFV, TDF and FTC.
1B
8.1.2.2 Rationale
1B
Preferred antiretroviral therapy. HIV-related TB
should be treated with a regimen, including rifamycin for
the full course of TB treatment, unless there is rifamycin
resistance or intolerance. Rifamycins frequently interact
with ARV medications and can lead to similar toxicities,
notably rash and hepatitis. We recommend EFV as the
preferred therapy for ART because of its confirmed
potency when used in TB/HIV coinfection [8–10], and its
efficacy in RCT. We recommend that EFV be given with
TDF and FTC due to the availability of a once-daily
co-formulation, a reduced risk of rash compared with NVP
and improved efficacy at higher HIV VLs (commonly
occurring in this setting). ABC-3TC is an alternative
acceptable NRTI backbone in patients with lower
HIV VLs and that are HLA-B*57:01 negative (see Section
5.3 Which NRTI backbone).
There is significant variability in the effect that
rifampicin has on EFV concentrations because of liver
enzyme induction, especially of CYP450 3A4 [8,11–13].
Subtherapeutic EFV concentrations may occur among
patients who weigh more than 60 kg who are taking
standard dose EFV together with rifampicin, and increasing
the dose of EFV from 600 mg daily to 800 mg daily may be
necessary; however, there is a risk of increasing adverse
effects. A cohort study and a small RCT have shown that
the standard adult EFV dose (600 mg daily) together with
two NRTIs is well tolerated and was efficacious in achieving complete viral suppression among adults on concomitant rifampicin-based TB treatment, although the majority
of patients were of low body weight [9,10,14].
In summary, we recommend that when EFV is used with
rifampicin, and in patients over 60 kg, the EFV dose is
increased to 800 mg daily. Standard doses of EFV are
recommended if the patient weighs <60 kg. We suggest that
TDM be performed at about the week of starting EFV if side
effects occur and the dose adjusted accordingly.
Protease inhibitors. When co-administered with
rifampicin, concentrations of standard-dose PIs are
decreased below therapeutic targets and cannot, therefore be
recommended [17–19]. Changing the dosing of PI/r
has resulted in unacceptable rates of hepatotoxicity [20–22].
Rifabutin has little effect on the concentrations of PI/r
but rifabutin concentrations are increased when the drug is
taken together with PIs. Current recommendations are to
give rifabutin at a dose of 150 mg thrice weekly to adults
taking PI/r. Some data suggest that 150 mg once daily can
be given to reduce the theoretical risk of rifamycin resistance due to subtherapeutic rifabutin concentrations, but
this strategy may be associated with increased side effects
[23–30].
Nevirapine. NVP taken with TB treatment is complicated by pharmacokinetic interactions and by overlapping toxicities, especially skin rash and hepatitis. One study
showed that patients co-infected with HIV and TB who
initiated NVP-based ART during TB treatment had a nearly
twofold higher risk of having a detectable HIV VL after
6 months compared with those taking NVP who did not
have TB. However, those patients who were established on
NVP at the time of initiation of TB treatment did not have
a higher risk of HIV virological failure [11]. Using a higher
maintenance dose of NVP (300 mg bd) to overcome drug
interactions has been associated with higher rates of hepatotoxicity [15]. In one randomized trial comparing NVP
200 mg twice daily at initiation with EFV 600 mg once
daily among patients with TB and HIV and CD4 cell counts
<250 cells/mL, non-inferiority of NVP was not demonstrated compared with EFV [16].
4 Havlir DV, Kendall MA, Ive P et al. Timing of antiretroviral
therapy for HIV-1 infection and tuberculosis. N Engl J Med
2011; 365: 1482–1491.
5 Blanc F-X, Sok T, Laureillard D et al. Earlier versus later
start of antiretroviral therapy in HIV-infected adults with
tuberculosis. N Engl J Med 2011; 365: 1471–1481.
6 Gazzard BG, on behalf of the BHIVA Treatment Guidelines
treatment of HIV-1-infected adults with antiretroviral
therapy 2008. HIV Med 2008; 9: 563–608.
7 Torok ME, Yen NT, Chau TT et al. Timing of initiation of
antiretroviral therapy in human immunodeficiency virus
(HIV)-associated tuberculous meningitis. Clin Infect Dis 2011;
52: 1374–1383.
8 Friedland G, Khoo S, Jack C et al. Administration of
efavirenz (600 mg/day) with rifampicin results in highly
variable levels but excellent clinical outcomes in patients
Other drugs. There are few clinical data to support
the use of newer NNRTIs, INIs and CCR5 receptor antagonists with rifampicin or rifabutin. We recommend that
physicians review pharmacokinetic and other data summarized in the current BHIVA guidelines for treatment of
TB/HIV coinfection [1].
8.1.3 References
1 Pozniak AL, Coyne KM, Miller RF et al.; BHIVA Guidelines
Subcommittee. British HIV Association guidelines for the
treatment of TB/HIV coinfection 2011. HIV Med 2011; 12:
517–524.
2 Dean GL, Edwards SG, Ives NJ et al. Treatment of
tuberculosis in HIV-1 infected persons in the era
of highly active antiretroviral therapy. AIDS 2002; 16:
75–83.
3 Abdoolkarim SS, Naidoo K, Grobler A et al. Timing of
initiation of antiretroviral drugs during tuberculosis therapy.
N Engl J Med 2010; 362: 697–706.
treated for tuberculosis and HIV. J Antimicrob Chemother
19 Ribera E, Azuaje C, Lopez RM et al. Pharmacokinetic
2006; 58: 1299–1302.
9 Manosuthi W, Kiertiburanakul S, Sungkanuparph S
interaction between rifampicin and the once-daily
combination of saquinavir and low-dose ritonavir in
et al. Efavirenz 600 mg/day versus efavirenz
HIV-infected patients with tuberculosis. J Antimicrob
800 mg/day in HIV-infected patients with tuberculosis
Chemother 2007; 59: 690–697.
receiving rifampicin: 48 weeks results. AIDS 2006; 20:
131–132.
20 Schmitt C, Riek M, Winters K, Schutz M, Grange S.
Unexpected hepatotoxicity of rifampin and
saquinavir/ritonavir in healthy male volunteers. Arch Drug
Inf 2009; 2: 8–16.
10 Boulle A, Van Cutsem G, Cohen K et al. Outcomes of
nevirapine- and efavirenz-based antiretroviral therapy when
co-administered with rifampicin-based antitubercular
21 Haas DW, Koletar SL, Laughlin L et al. Hepatotoxicity and
gastrointestinal intolerance when healthy volunteers taking
therapy. JAMA 2008; 300: 530–539.
rifampin add twice-daily atazanavir and ritonavir. J Acquir
11 Lopez-Cortes LF, Ruiz-Valderas R, Viciana P et al.
Pharmacokinetic interactions between efavirenz and
rifampicin in HIV-infected patients with tuberculosis. Clin
22 Nijland HM, l’homme RF, Rongen GA et al. High incidence
of adverse events in healthy volunteers receiving rifampicin
and adjusted doses of lopinavir/ritonavir tablets. AIDS 2008;
Pharmacokinet 2002; 41: 681–690.
12 Manosuthi W, Sungkanuparph S, Thakkinstian A et al.
Efavirenz levels and 24-week efficacy in HIV-infected
patients with tuberculosis receiving highly active
antiretroviral therapy and rifampicin. AIDS 2005; 19:
1481–1486.
13 Ngaimisi E, Mugusi S, Minzi O et al. Effect of rifampicin
and CYP2B6 genotype on long-term efavirenz auto
induction and plasma exposure in HIV patients with or
without tuberculosis. Clin Pharmacother 2011; 90:
406–413.
14 Manosuthi W, Sungkanuparph S, Tantanathip P et al. A
randomized trial comparing plasma drug concentrations and
efficacies between 2 nonnucleoside reverse-transcriptase
22: 931–935.
23 Narita M, Stambaugh JJ, Hollender ES et al. Use of rifabutin
with protease inhibitors for human immunodeficiency
virus-infected patients with tuberculosis. Clin Infect Dis
2000; 30: 779–783.
24 Boulanger C, Hollender E, Farrell K et al. Pharmacokinetic
evaluation of rifabutin in combination with
lopinavir-ritonavir in patients with HIV infection
and active tuberculosis. Clin Infect Dis 2009; 49:
1305–1311.
25 Jenny-Avital ER, Joseph K. Rifamycin-resistant
Mycobacterium tuberculosis in the highly active
antiretroviral therapy era: a report of 3 relapses with
inhibitor-based regimens in HIV-infected patients receiving
rifampicin: the N2R Study. Clin Infect Dis 2009; 48:
1752–1759.
15 Avihingsanon A, Manosuthi W, Kantipong P et al.
Pharmacokinetics and 48-week efficacy of nevirapine:
400 mg versus 600 mg per day in HIV-tuberculosis
co-infection receiving rifampicin. Antivir Ther 2008; 13:
529–536.
16 Bonnet M, Bhatt N, Baudin E et al. Results of the
CARINEMO-ANRS 12146 randomized trial comparing the
efficacy and safety of nevirapine versus efavirenz for
treatment of HIV-TB co-infected patients in Mozambique.
6th IAS Conference on HIV Pathogenesis, Treatment,
and Prevention. Rome, Italy. August 2011 [Abstract
WELBX05].
17 Laporte C, Colbers E, Bertz R et al. Pharmacokinetics of
adjusted-dose lopinavir-ritonavir combined with rifampin in
healthy volunteers. Antimicrob Agents Chemother 2004; 48:
1553–1560.
18 Acosta EP, Kendall MA, Gerber JG et al. Effect of
concomitantly administered rifampin on the
pharmacokinetics and safety of atazanavir administered
twice daily. Antimicrob Agents Chemother 2007; 51:
3104–3110.
acquired rifampin resistance following alternate-day
rifabutin and boosted protease inhibitor therapy. Clin Infect
Dis 2009; 48: 1471–1474.
26 Naiker S, Conolly C, Weisner L et al. Pharmacokinetic
evaluation of different rifabutin dosing strategies in African
27
28
29
30
TB patients on lopinavir/ritonavir-based ART. 18th
Boston, MA. February 2011 [Abstract 650].
Weiner M, Benator D, Burman W et al. Association
between acquired rifamycin resistance and the
pharmacokinetics of rifabutin and isoniazid among patients
with HIV and tuberculosis. Clin Infect Dis 2005; 40:
1481–1491.
Khachi H, O’Connell R, Ladenheim D, Orkin C.
Pharmacokinetic interactions between rifabutin and
lopinavir/ritonavir in HIV-infected patients with
mycobacterial co-infection. J Antimicrob Chemother 2009;
64: 871–873.
Tseng AL, Walmsley SL. Rifabutin-associated uveitis. Ann
Pharmacother 1995; 29: 1149–1155.
Cato A 3rd, Cavanaugh J, Shi H et al. The effect of multiple
doses of ritonavir on the pharmacokinetics of rifabutin. Clin
Pharmacol Ther 1998; 63: 414–421.
8.2 HIV and viral hepatitis coinfection
8.2.1 Introduction
The following guidance provides a brief summary of the
key statements and recommendations regarding prescribing ART in patients with HIV/hepatitis B and C coinfection.
It is based on the BHIVA guidelines for the management
of hepatitis viruses in adults infected with HIV 2013
[1], which should be consulted for further information and
to the BHIVA web site for latest updates (http://www
.bhiva.org/publishedandapproved.aspx).
Where viral hepatitis B or C chronic infection has been
diagnosed, all individuals should be referred and subsequently managed by a clinician experienced in the management of both HIV and hepatitis or should be jointly managed
by clinicians from HIV and hepatitis backgrounds. Those
with end-stage liver disease (ESLD) should be managed in
centres where potential complications can be dealt with and
where a close link to a transplant unit exists.
8.2.1.1 Summary of when to start recommendations
CD4 cell
count
(cells/mL)
HBV
requiring
treatment*
HBV not
requiring
treatment
>500
Start ART (1C)
(Include TDF
and FTC)
Consider
ART (2C)
(Include
TDF and
FTC)
Start ART
(1B) (Include
TDF and FTC)
ⱕ500
Start ART (1B)
(Include TDF
and FTC)
HCV with
immediate
plan to
start HCV
treatment*
HCV with no
immediate
plan to
start HCV
treatment
Consider ART
before HCV
treatment
commenced
(2C)
Start ART before
HCV treatment
commenced (1C)
Discuss with HIV
and viral hepatitis
specialist
Consider
ART (2D)
Start
ART (1C)
*See BHIVA guidelines for the management of hepatitis viruses in adults
infected with HIV 2013 [1] for indications to treat hepatitis B and C
8.2.2 Hepatitis B
8.2.2.1 When to start antiretroviral therapy
Recommendations
• We recommend patients with HIV and hepatitis B virus
coinfection who have a CD4 cell count <500 cells/mL are
treated with fully suppressive ART inclusive of anti-HBV
active antivirals (1B).
• We recommend patients with HIV and HBV coinfection who
have a CD4 cell count ⱖ500 cells/mL and who have an
HBV-DNA ⱖ2000 IU/mL and/or evidence of more than
minimal fibrosis (Metavir ⱖF2) are treated with fully suppressive ART inclusive of anti-HBV active antivirals (1C).
Auditable measure. Proportion of patients with a
CD4 cell count ⱖ500 cells/mL and an HBV DNA
ⱖ2000 IU/mL and/or evidence of more than minimal fibrosis commencing ART inclusive of anti-HBV antivirals.
Rationale. Because of the negative effect of immune
depletion on HBV disease progression, the availability of
single drugs with high level dual hepatitis B and HIV
antiviral activity, and the increased risk of liver-related
deaths in patients with CD4 cell counts ⱖ500 cells/mL,
coinfected patients with active HBV disease (HBV viral load
ⱖ2000 IU/mL or Metavir F2 or above) and those with CD4
cell counts below 500 cells/mL should start ART inclusive
of anti-HBV active antivirals [2]. Patients with CD4 cell
counts ⱖ500 cells/mL and HBV DNA of <2000 IU/mL,
minimal or no evidence of liver inflammation or fibrosis,
and a repeatedly normal ALT should be given the option to
commence treatment or defer and be monitored not less
than 6-monthly with HBV DNA and ALT and at least yearly
for evidence of fibrosis.
For more information on the indications to start treatment for hepatitis B infection please refer to the BHIVA
guidelines for the management of hepatitis viruses in adults
infected with HIV 2013 [1].
8.2.2.2 What to start
Recommendations
• We recommend TDF/FTC as part of a fully suppressive
ART combination should be given to all patients where
HBV treatment is deemed necessary (1C).
• We recommend neither 3TC nor FTC be used as the sole
active drug against HBV in ART due to the rapid emergence of HBV resistant to these agents (1B).
• We recommend 3TC/FTC may be omitted from the ART
regimen and tenofovir be given as the sole anti-HBV
active agent if there is clinical or genotypic evidence of
3TC/FTC-resistant HBV or HIV (1D).
Auditable measures. Proportion of patients with a
CD4 cell count <500 cells/mL receiving TDF/FTC or TDF/
3TC as part of a fully suppressive combination ART
regimen.
Proportion of patients receiving 3TC or FTC as the sole
active drug against HBV in ART.
Rationale. TDF, FTC and 3TC are agents that have
good antiviral activity against both HIV and hepatitis B.
The efficacy of these drugs against hepatitis B has been
assessed in randomized trials extending out to 5 years in
mono-infected patients [3]. They are recommended agents
in these guidelines for the treatment of HIV-1 infection.
All hepatitis B coinfected individuals who start ART,
should commence a regimen containing TDF and FTC.
Hepatitis B treatment options for patients declining ART
are discussed elsewhere [1].
If an individual becomes intolerant or is unable to commence a TDF-containing regimen, entecavir should be used
if retaining activity. Because entecavir demonstrates modest
anti-HIV activity and can select for HIV resistance, it should
only be used in addition to a fully suppressive combination
ART regimen. No individual coinfected with hepatitis B
should receive a regimen containing 3TC or FTC monotherapy as its use may result in the selection of the YMDD
mutation [4,5]. TDF resistance has not been clearly described
and resistance is unlikely to provide an explanation for most
cases of suboptimal responses to TDF. In combination with
3TC or FTC, it has been demonstrated to be effective at
suppressing HBV DNA, inducing HBeAg seroconversion,
and reducing the risk of HBV breakthrough [6].
Where there is primary non-response or partial response
to HBV-active antivirals, or where there is virological
breakthrough, assessment of drug adherence and HBV
resistance testing should be undertaken. Coinfected individuals who need to start a new ART regimen for reasons
such as ART virological failure should ensure that effective
anti-hepatitis B therapy is continued in addition to their
new ART regimen. Abrupt withdrawal of effective treatment may lead to a flare in hepatitis B replication with liver
damage. This may be particularly severe in patients with
cirrhosis.
Auditable measure Proportion of patients with a
CD4 cell count <500 cells/mL commencing ART.
Rationale. HIV has an impact on hepatitis C infection. Individuals with HCV coinfection have higher HCV
viral loads, faster rates of fibrosis progression and an
increased risk of cirrhosis compared to those with HCV
alone. End-stage liver disease, HCC and liver-related death
occur more frequently, at an earlier age, and within a
shorter time period with the risk of liver-related mortality
and HCC increasing as the CD4 cell count declines. Successful treatment outcome with pegylated interferon (PEGIFN) and ribavirin (RBV) lessens as the CD4 cell count
declines and although ART slows the progression of liver
disease it is still faster than in HCV monoinfection.
For these reasons, patients with HIV and hepatitis C
infection with CD4 cell counts <500 cells/mL should start
ART. This should be immediate irrespective of whether HCV
treatment is planned or not. For patients with CD4 cell
counts between 350 and 500 cells/mL, initiation of antiHCV treatment should be delayed until after start of ART
unless there is an urgent indication for anti-HCV treatment
when ART should be commenced as soon as the patient has
been stabilized on HCV therapy.
Individuals with a CD4 cell count greater than
500 cells/mL who defer hepatitis C therapy, should be given
the option to commence ART. If they opt to defer, they
should be monitored closely for HIV or hepatitis C disease
progression, including at least an annual assessment of
liver fibrosis.
8.2.3 Hepatitis C
8.2.3.1 When to start antiretroviral therapy
Recommendations
• We recommend all patients with HIV and hepatitis C
virus coinfection be assessed for HCV treatment (GPP).
• We suggest commencing ART when the CD4 cell count is
greater than 500 cells/mL in all patients who are not to
commence HCV treatment immediately (2D).
• We recommend commencing ART when the CD4 cell
count is less than 500 cells/mL in all patients who are not
to commence anti-HCV treatment immediately (1B).
• We recommend commencing ART to optimize immune
status before anti-HCV therapy is initiated when the CD4
cell count is between 350 and 500 cells/mL unless there
is an urgent indication for anti-HCV treatment when
ART should be commenced as soon as the patient has
been stabilized on HCV therapy (GPP).
• We recommend commencing ART to allow immune
recovery before anti-HCV therapy is initiated when the
CD4 cell count is less than 350 cells/mL (GPP).
8.2.3.2 What to start
Recommendations
• We recommend if patients are commencing ART, and
DAAs are not being considered, standard first-line ART
should be commenced (GPP).
• We recommend when DAAs are to be used there is
careful consideration of possible DDIs (1C) and current
or archived HIV resistance. All drug interactions should
be checked with an expert source (e.g., www.hiv
-druginteractions.org).
• We recommend if boceprevir is to be used, RAL with TDF
plus FTC should be the treatment of choice for those with
wild-type HIV (1C): pharmacokinetic data would support
ETV, RPV and MVC as alternatives.
• We recommend if telaprevir is to be used either RAL or
standard-dose ATV/r should be used (1C): pharmacokinetic data would support ETV, RPV and MVC as alternatives. EFV may be used but the telaprevir dose needs
to be increased to 1125 mg tds.
• We suggest that if ABC is to be used with ribavirin, the
ribavirin should be weight-based dose-adjusted (2C).
Auditable measure. Among patients receiving
DAAs for HCV genotype 1 with ART for wild type HIV, the
percentage on a recommended regimen, i.e. RAL with TDF
plus FTC with boceprevir; or RAL or boosted ATV with
standard dose telaprevir; or EFV with increased dose
1125 mg tds telaprevir.
Rationale. When DAAs are chosen, some restriction
on first-line ARV choice exists due to drug–drug interactions. Boceprevir and telaprevir are currently licensed
DAAs for the treatment of hepatitis C genotype 1 infection
and are substrates and inhibitors of cytochrome P (CYP)
3A4/5 and p-glycoprotein (p-gp), and therefore interact
with several ARVs. Boceprevir is also metabolized by aldoketoreductase. Choice of available, safe third agents differs
with use of boceprevir and telaprevir. From the limited data
and drug–drug interaction studies, we recommend that if
boceprevir is to be used, RAL with TDF/FTC should represent first-line ART in the presence of wild-type HIV. For
telaprevir, we recommend that standard-dose ATV/r or RAL
should be used – EFV can also be used but telaprevir dose
needs to be increased to 1125 mg tds. Alternative ARVs
when treating with either boceprevir or telaprevir are ETV,
RPV and MVC, based on available pharmacokinetic (PK)
data. Multiple DAAs are currently in Phase III trials in
coinfected patients. Each drug has particular DDIs when
combined with ART agents, and expert opinion should be
sought on possible PK interactions. Clinicians should refer
to an online information resource (such as http://www.hep
-druginteractions.org) or seek expert opinion on possible
PK interactions.
8.2.4 References
1 Wilkins E , Nelson M for the BHIVA Hepatitis Guidelines
management of hepatitis viruses in adults infected with HIV
2013. HIV Medicine 2013; 14 (Suppl 4): 1–71.
8.3 HIV-related cancers
Proportion of patients with an AIDS-defining malignancy
on ART.
Proportion of patients with a non-AIDS-defining malignancy on ART.
Record in patient’s notes of potential pharmacokinetic
drug interactions between ARVs and systemic anticancer
therapy.
8.3.2 When to start antiretroviral therapy: AIDS-defining
malignancies
KS, high-grade B-cell NHL and invasive cervical cancer are
all AIDS-defining illnesses and are thus indications to
commence ART regardless of CD4 cell count or HIV VL.
8.3.2.1 Kaposi sarcoma
Recommendation
• We recommend starting ART in HIV-positive patients
with KS (1A).
Rationale. ART has been shown to reduce the incidence of KS in HIV cohort studies [1–4], to prevent KS in
patients on ART [3], and, in addition, increases the time to
disease progression in KS [5], improves prognosis in KS
and prolongs survival in KS [6–8]. When initiating ART for
KS, there appears to be no difference in response or
outcome of KS between different HIV treatment regimens
[3,9]. Therefore, no recommendation can be made on
choice of HIV therapy for patients with KS.
8.3.2.2 Non-Hodgkin lymphoma
Recommendation
with NHL (1B).
Rationale. ART has been shown to reduce the incidence of NHL [1,2,10–18] and to improve the outcome
[8,19–22]. Before ART was available, the treatment of NHL
with standard doses of chemotherapy produced marked
toxicity and a high incidence of opportunistic infections
[23]. In an attempt to decrease toxicity, modified-dose
chemotherapy regimens were used by the AIDS Clinical
Trials Group (ACTG). However, the reduced opportunistic
infections were offset by the lower response rates [24]. Since
the widespread availability of ART, two retrospective studies
reported higher tumour response rates and overall survival
in HIV seropositive patients with systemic NHL who were
treated with CHOP chemotherapy and concomitant ART
compared with those who were treated with CHOP alone
[19,20]. Similarly, in a separate study of liposomal doxorubicin in combination with cyclophosphamide, vincristine
and prednisolone in HIV-associated NHL, improvement
in survival was associated with HIV viral control, although
complete remission rates were independent of HIV VL
[25].
Further evidence to support the use of ART with chemotherapy in both KS and NHL is the finding from historical
comparisons that the fall in CD4 cell count during chemotherapy is less profound when ART is prescribed concomitantly and that the duration of lymphocyte subset
suppression is briefer [4,26–28].
However, a number of US intergroup studies have either
withheld ART during chemotherapy [29,30] or delayed the
initiation of ART [31]. The rationale for this approach
includes avoiding adverse pharmacokinetic and pharmacodynamic interactions between ART and chemotherapy and
the theoretical concern that PIs may inhibit lymphocyte
apoptosis and thus contribute to chemoresistance of lymphomas [32]. Although no new HIV mutations were identified, these studies were small and ART was promptly
reinstituted after abbreviated chemotherapy. Nevertheless,
it took 12–18 months after completing chemotherapy for
plasma HIV viraemia to become undetectable in many
patients [30]. Importantly, patients with NHL frequently
present with CD4 cell counts <200 cells/mL and thus the
reduction in CD4 cell count associated with systemic
chemotherapy and structured suspension of ART is not
ideal.
8.3.3 When to start antiretroviral therapy:
non-AIDS-defining malignancies
• We suggest starting ART in HIV-positive patients with
non-AIDS-defining malignancies (2C).
• We recommend starting ART in HIV-positive patients who
are commencing immunosuppressive radiotherapy or
chemotherapy for non-AIDS-defining malignancies (1C).
8.3.3.2 Rationale
While ART has little effect on the incidence of NADMs
[2,57–64] and there is no evidence that ART alone causes
regression of NADMs, the immunosuppressive effects of
both chemotherapy [4,26–28] and radiotherapy [47–50]
may justify starting ART in HIV-positive individuals
who are commencing systemic anticancer therapy or
radiotherapy.
8.3.4 What to start
8.3.2.3 Cervical cancer
Recommendation
• We suggest starting ART in HIV-positive patients with
cervical cancer (2C).
who are commencing radiotherapy or chemotherapy for
cervical cancer (1D).
Rationale. There is less clear evidence to support
starting ART in women diagnosed with invasive cervical
cancer, despite its status as an AIDS-defining illness.
Co-registration studies have shown that ART has not
reduced the incidence of cervical cancer [33–35], moreover
the effects of ART on pre-invasive cervical dysplasia have
been variable with some studies suggesting that ART
causes regression of cervical intraepithelial neoplasia
[36–42] and others showing no beneficial effect of ART
[43–46]. The effects of ART on outcomes in HIV-positive
women with invasive cervical cancer have not been
reported but analogies with anal cancer may be drawn as
the malignancies share common pathogenesis and treatment modalities. Combined chemoradiotherapy in anal
cancer has been shown to cause significant and prolonged
CD4 suppression even when ART is administered concomitantly [47–50]. Similarly the toxicity of chemoradiotherapy
for HIV-associated anal cancer appears to be less profound
among patients given ART compared to historical controls
[48,49,51–56].
• We recommend that potential pharmacokinetic interactions between ARVs and systemic anticancer therapy are
checked before administration (with tools such as: http://
www.hiv-druginteractions.org) (GPP).
8.3.4.2 Rationale
Significant pharmacokinetic and pharmacodynamic interactions have been reported between ARV drugs and systemic anticancer therapies. The mechanisms of the
pharmacokinetic interactions include the inhibition and
induction by ARV agents of enzymes, especially the CYP450
family and uridine diphosphoglucuronosyl transferase
isoenzymes, involved in the catabolism and activation of
cytotoxic chemotherapy agents. In addition, competition for
renal clearance, intracellular phosphorylation and ABC
(ATP-binding cassette) transporters, has been hypothesized
to contribute to these drug interactions [65]. Similarly,
pharmacodynamic interactions, in particular overlapping
toxicities between ARVs and systemic anticancer therapy,
suggest that some drug combinations should be avoided in
patients with HIV-associated cancers. Much of the guidance
on the use of individual ARV agents with systemic anticancer therapy comes from reviews of potential drug interactions rather than from clinical studies [65–67]. The
pharmacokinetic interactions between ARVs and systemic
anticancer therapy are not confined to cytotoxic chemotherapy agents and extensive interactions with newer targeted therapies such as imatinib, erlotinib, sorafenib,
bortezomib and temsirolimus have been described [67].
• We suggest avoiding ritonavir-boosted ART in HIVpositive patients who are to receive cytotoxic chemotherapy agents that are metabolized by the CYP450
enzyme system (2C).
8.3.4.4 Rationale
In general, clinically important pharmacokinetic drug
interactions with systemic anticancer therapies are most
common with PI/r-based ART and most clinicians avoid
these combinations where possible. For example, in a
cohort study, the rates of severe infections and severe
neutropenia following chemotherapy for AIDS-related
NHL were significantly higher among patients receiving
concomitant PI (mainly ritonavir boosted) than in those
on NNRTI-based ART regimens, although there was no
difference in survival between the groups [68]. Furthermore, case reports of clinically significant life-threatening
interactions between ritonavir-boosted-based ART and
docetaxel [69], irinotecan [70] and vinblastine [71] have
been published.
• We recommend against the use of ATV in HIV-positive
patients who are to receive irinotecan (1C).
8.3.4.6 Rationale
The camptothecin cytotoxic agent irinotecan is extensively
metabolized by uridine diphosphoglucuronosyl transferase
1A1 isoenzymes that are inhibited by ATV [72]. In patients
with Gilbert’s syndrome, who have a congenital deficiency
of uridine diphosphoglucuronosyl transferase 1A1, irinotecan administration has led to life-threatening toxicity [73].
• We suggest avoiding ARV agents in HIV-positive
patients who are to receive cytotoxic chemotherapy
agents that have overlapping toxicities (2C).
8.3.4.8 Rationale
Both ARV agents and systemic anticancer therapies have
substantial toxicity and where these overlap it is likely
that the risk of toxicity is greater. For example, ZDV
commonly causes myelosuppression and anaemia [74],
which are also frequent side effects of cytotoxic chemotherapy and so these should not be co-prescribed where
possible. Similarly, dideoxynucleosides cause peripheral
neuropathy [75], a common toxicity of taxanes and vinca
alkaloids, so co-prescribing should be avoided. Both ZDV
and dideoxynucleosides are no longer recommended for
initiation of ART but some treatment-experienced patients
may still be receiving these drugs and alternatives should
be considered.
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50 Alfa-Wali M, Allen-Mersh T, Antoniou A et al.
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52 Oehler-Janne C, Huguet F, Provencher S et al. HIV-specific
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44 Moore AL, Sabin CA, Madge S et al. Highly active
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46 Sirera G, Videla S, Lopez-Blazquez R et al. Highly
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8.4 HIV-associated neurocognitive impairment
8.4.1 Introduction
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With the widespread use of effective combination ART, the
incidence of severe HIV-associated cerebral disease has
declined dramatically [1]; however, more subtle forms of
brain disease, known as HIV-associated NC disorders are
reported to remain prevalent [2]. This NC deficit may
present with a wide spectrum of clinical symptoms, but
typically includes patterns involving ineffective learning
and problems with executive function, rather than pure
difficulties in formulating new memory (the cortical defect
typical of Alzheimer’s disease [3]).
Given the changing picture of this disease, a revised
nomenclature system has been proposed classifying subjects with abnormal neuropsychological testing results in
to three categories based on patient’s symptoms, measured via the activities of daily living scale [2]. Subjects
with abnormal neuropsychiatric testing results, who are
otherwise asymptomatic, are classified as having HIVassociated asymptomatic NC impairment; those who are
mildly symptomatic are classified as having HIVassociated mild NC disorder; and those who are severely
symptomatic are classified as having HIV-associated
dementia. The clinical relevance of asymptomatic NC
impairment, namely asymptomatic subjects with abnormal results on neuropsychological testing, remains
unclear.
Reports describing rates of NC impairment vary with
some groups describing that up to 50% of HIV-positive
subjects meet the above diagnostic criteria [4]. However,
such reports should be interpreted with caution as asymptomatic subjects are often included and not all reports
correct for effective ARV use. A Swiss cohort has reported
19% of aviraemic HIV-positive subjects meet the classification for mild NC disorder or above [5].
Risk factors for the development of NC disorders are
poorly understood and are likely to be multifactorial,
including both HIV disease factors [6] and concomitant
diseases [7]. Although it is possible the choice of combination ART a subject receives may influence NC function,
this is a controversial area without definitive evidence. The
following recommendations apply to patients with symptomatic HIV-associated NC disorders.
• We recommend patients with symptomatic HIVassociated NC disorders start ART irrespective of CD4
lymphocyte count (1C).
symptomatic HIV-associated NC disorders on ART.
8.4.2.2 Rationale
Current evidence suggests NC function improves after
commencing ART for the first time [8] in both cognitively
symptomatic [9] and asymptomatic [10] subjects. However,
these studies have been undertaken in individuals with
other indications to commence ART, in general with CD4
lymphocyte counts in the designated range where treatment is recommended. For subjects with higher CD4
lymphocyte counts, the ongoing START study will prospectively assess NC function in HIV-positive subjects commencing ART at an earlier stage of HIV disease.
Therefore, ART is recommended in NC symptomatic subjects whose CD4 lymphocyte count itself is an indication to
commence therapy.
In the absence of scientific data, in cognitively symptomatic subjects with higher CD4 lymphocyte counts in
whom ART would not be otherwise indicated, a recommendation to consider commencing ART is based (i) on
observed improvements in cognitive function reported in
subjects with lower CD4 lymphocyte counts commencing
therapy [8], and (ii) to avoid a future decline in CD4
lymphocyte count in such subjects, given the welldescribed association between low nadir CD4 lymphocyte
count and NC impairment [6].
Suboptimal adherence to therapy may occur
more frequently in subjects with NC impairment, hence
adequate support services to optimize adherence are
essential.
8.4.3 What to start
• We recommend patients with HIV-associated NC disorders start standard combination ART regimens (1C).
HIV-associated NC disorders on ART containing two NRTIs
and one of an NNRTI, a PI/r or an INI.
8.4.3.2 Rationale
Although during the earlier years of ART, clear benefits on
cerebral function of individual ARV drugs such as ZDV
were reported [11] and the benefits of combination therapy
overall are well described [8], data are sparse regarding any
differences in these benefits between individual agents or
combinations. Within cohort studies, the use of the NRTI
class within ARV regimens has been associated with a
reduced risk of severe HIV-associated dementia [12] com-
pared with the use of other regimens; however, the confounders of a cohort study limit interpretation of these
data.
Recently, attempts have been made to establish a relationship between cognitive function and CNS ARV drug
delivery based on an ARV scoring system known as the
clinical penetration effectiveness (CPE) score [13]. The CPE
score aims to rationally score the cerebral effects of individual ARV agents. However, the system is predominantly
designed around pharmacokinetic modelling rather than
pharmacodynamic endpoints such as data describing
changes in NC function. Studies that have assessed the
correlation between the CPE scores of ARV regimens with
NC function report conflicting findings with some cohorts
reporting a positive association [14,15], and others describing a negative association [16]. Given the potential flaws
outlined in the design of the CPE score, a lack of prospective clinical data and discrepancies in findings within
cohort studies, the CPE score should not influence therapeutic decisions in subjects with NC impairment commencing ART.
One small prospective study has assessed the cerebral
effects of three different ARV regimens in neurologically
asymptomatic subjects reporting greater improvement in
NC function in subjects commencing a quadruple nucleoside regimen compared with an EFV- or ATV/r-containing
regimen [17]. However, subjects were asymptomatic from a
neurological point of view, limiting the relevance of these
findings to neurologically symptomatic subjects.
The improvements in NC function observed with ZDV
monotherapy [11] and the greater improvements in NC
function observed with a ZDV-containing quadruple nucleoside regimen compared with other ART regimens [17],
raise the possibility of selecting a ZDV-containing ARV
regimen in subjects with NC impairment. Conversely, a lack
of comparator data for ZDV monotherapy and potential
toxicities arising from ZDV use may limit the relevance of
these data. Of note, further to peripheral toxicities, which
are well described with ZDV use, biomarker data suggest
there may also be CNS toxicities associated with the use of
ZDV-containing regimens [18].
In summary, we recommend patients with NC impairment start standard combination ART regimens and the
choice should be determined, as with other patients, by
different factors, including baseline VL, side effect profile,
tolerability, DDIs and patient preference.
8.4.3.3 Novel antiretroviral strategies and NC function
Novel ARV strategies, including protease-inhibitor monotherapy continue to be assessed in clinical trials as costbeneficial treatment regimens with the potential for
reduced long-term toxicities. Concerns have been raised
regarding the cerebral effects of PI monotherapy [19], with
such concerns based on the hypotheses that PI monotherapy comprises only one effective ARV agent that may
not adequately suppress ongoing HIV replication in sanctuary sites such as the CNS, and on pharmacokinetic
modelling that suggests that not all PIs have optimal penetration across the blood–brain barrier [13]. Furthermore,
isolated cases describing the evolution of CNS disease in
previously stable HIV-positive subjects receiving PI monotherapy have been reported [20].
One study was specifically designed to assess the cerebral effects of LPV/r monotherapy [21]; however, it was
terminated early due to a lack of efficacy in the plasma
compartment. Although cases of CNS disease were reported
within this study, such results must be interpreted with
caution as virological endpoints in the plasma compartment were not met and therefore such cases may be driven
by poor ARV efficacy per se, rather than distinct CNS
disease itself [22].
In the MONET study assessing DRV/r vs. standard
therapy, no differences in patient-reported cognitive function are observed between the study treatment arms over 3
years of therapy [23]. Although reassuring, these data represent changes in patient-reported observations rather than
observations from formal neuropsychological testing.
Interestingly, in a small substudy within MONET, improvements in detailed neuropsychological testing and improvements in cerebral biomarkers measured via imaging
techniques, were reported in both treatment arms [24].
In the ongoing UK PIVOT study, detailed neuropsychological testing is being assessed prospectively in subjects
on PI monotherapy vs. standard therapy, the results of
which will be of great interest to this field.
Given the above theoretical concerns regarding the CNS
activity of PI monotherapy, and for the majority of HIVpositive subjects it may be possible to select other ARV
regimens, we suggest this approach is currently avoided in
neurologically symptomatic subjects.
8.4.4 Modification of antiretroviral therapy
In patients with ongoing or worsening NC impairment
despite ART, we recommend the following best practice
management (GPP):
• Reassessment for confounding conditions.
• Assessment of CSF HIV RNA, CSF HIV genotropism and
genotyping of CSF HIV RNA.
• In subjects with detectable CSF HIV RNA, modifications
to ART should be based on plasma and CSF genotypic
and genotropism results.
8.4.4.2 Rationale
Several published randomized controlled studies, assessing
both intensification of ART with a new ARV agent [25] and
with adjunctive therapies [26–29] have been published.
Unfortunately, none of these studies describe improvements in cognition subsequent to the study interventions.
Without evidence-based interventions, the Writing Group
outlines below a best practice approach based on the
current literature.
As HIV-associated NC disorders are a diagnosis of exclusion, re-evaluation of subjects with ongoing NC impairment despite ART for confounding conditions, with expert
input from other clinical specialties such as psychiatry,
neurology and neuropsychology, is recommended and,
where possible, input from an HIV neurology service.
Assessment of CSF HIV RNA, CSF HIV genotropism
and genotypic analysis of CSF RNA may be useful tools
in the management of subjects with ongoing NC for the
following reasons. First, data from cohorts of untreated
HIV-positive subjects would suggest CSF HIV RNA to be
greater in subjects with HIV-associated dementia and
cognitive decline [30,31] and therefore suppression of
CSF HIV RNA may be beneficial for cognitive function.
Secondly, in subjects with ongoing NC impairment,
higher degrees of genetic diversity between HIV viral
strains in the CSF and plasma compartment may exist
[32], even in subjects with undetectable plasma HIV RNA
[33]. Therefore, assessment for CSF HIV resistance may be
worthwhile to tailor ART.
8.4.5 References
1 Dore GJ, Correll PK, Li Y et al. Changes to AIDS dementia
complex in the era of highly active antiretroviral therapy.
AIDS 1999; 13: 1249–1253.
2 Antinori A, Arendt G, Becker JT et al. Updated research
nosology for HIV-associated neurocognitive disorders.
Neurology 2007; 69: 1789–1799.
3 Valcour V, Paul R, Chiao S, Wendelken LA, Miller B.
Screening for cognitive impairment in human
immunodeficiency virus. Clin Infect Dis 2011; 53:
836–842.
4 Heaton RK, Clifford DB, Franklin DR Jr et al. HIV-associated
neurocognitive disorders persist in the era of potent
antiretroviral therapy: CHARTER Study. Neurology 2011; 75:
2087–2096.
5 Simioni S, Cavassini M, Annoni JM et al. Cognitive
dysfunction in HIV patients despite long-standing
suppression of viremia. AIDS 2010; 24: 1243–1250.
6 Ellis RJ, Badiee J, Vaida F et al. CD4 nadir is a predictor of
HIV neurocognitive impairment in the era of combination
antiretroviral therapy. AIDS 2011; 25: 1747–1751.
7 Wright EJ, Grund B, Robertson K et al. Cardiovascular risk
factors associated with lower baseline cognitive performance
in HIV-positive persons. Neurology 2011; 75: 864–873.
8 Al-Khindi T, Zakzanis KK, van Gorp WG. Does antiretroviral
therapy improve HIV-associated cognitive impairment? A
quantitative review of the literature. J Int Neuropsychol Soc
2011; 17: 1–14.
9 Cysique LA, Vaida F, Letendre S et al. Dynamics of cognitive
change in impaired HIV-positive patients initiating
antiretroviral therapy. Neurology 2009; 73: 342–348.
10 Winston A, Puls R, Kerr SJ et al. Dynamics of cognitive
change in HIV-infected individuals commencing three
different initial antiretroviral regimens: a randomized,
controlled study. HIV Med 2012; 13: 245–251.
11 Schmitt FA, Bigley JW, McKinnis R et al. Neuropsychological
outcome of zidovudine (AZT) treatment of patients with
AIDS and AIDS-related complex. N Engl J Med 1988; 319:
1573–1578.
12 d’Arminio Monforte A, Cinque P, Mocroft A et al.
Changing incidence of central nervous system
diseases in the EuroSIDA cohort. Ann Neurol 2004; 55:
320–328.
13 Letendre S, Marquie-Beck J, Capparelli E et al. Validation of
the CNS Penetration-Effectiveness rank for quantifying
antiretroviral penetration into the central nervous system.
Arch Neurol 2008; 65: 65–70.
14 Tozzi V, Balestra P, Salvatori MF et al. Changes in cognition
during antiretroviral therapy: comparison of 2 different
ranking systems to measure antiretroviral drug efficacy on
HIV-associated neurocognitive disorders. J Acquir Immune
Defic Syndr 2009; 52: 56–63.
15 Smurzynski M, Wu K, Letendre S et al. Effects of central
nervous system antiretroviral penetration on cognitive
functioning in the ALLRT cohort. AIDS 2011; 25:
357–365.
16 Marra CM, Zhao Y, Clifford DB et al. Impact of combination
antiretroviral therapy on cerebrospinal fluid HIV RNA
and neurocognitive performance. AIDS 2009; 23:
1359–1366.
17 Winston A, Duncombe C, Li PC et al. Does choice of
combination antiretroviral therapy (cART) alter changes in
cerebral function testing after 48 weeks in treatment-naive,
HIV-1-infected individuals commencing cART? A
randomized, controlled study. Clin Infect Dis 2010; 50:
920–929.
18 Schweinsburg BC, Taylor MJ, Alhassoon OM et al. Brain
mitochondrial injury in human immunodeficiency
virus-seropositive (HIV+) individuals taking nucleoside
reverse transcriptase inhibitors. J Neurovirol 2005; 11:
356–364.
19 Perez-Valero I, Bayon C, Cambron I, Gonzalez A,
Arribas JR. Protease inhibitor monotherapy and the CNS:
peace of mind? J Antimicrob Chemother 2011; 66:
1954–1962.
20 Katlama C, Valantin MA, Algarte-Genin M et al. Efficacy of
darunavir/ritonavir maintenance monotherapy in patients
with HIV-1 viral suppression: a randomized open-label,
noninferiority trial, MONOI-ANRS 136. AIDS 2010; 24:
2365–2374.
21 Gutmann C, Cusini A, Günthard HF et al. Randomized
controlled study demonstrating failure of LPV/r
monotherapy in HIV: the role of compartment and
CD4-nadir. AIDS 2010; 24: 2347–2354.
22 Paton NI, Meynard JL, Pulido F et al. Inappropriate claim of
′failure of ritonavir-boosted lopinavir monotherapy in HIV′
in the Monotherapy Switzerland/Thailand (MOST) trial. AIDS
2011; 25: 393–394.
23 Winston A, Fätkenheuer G, Arribas J et al. Neuropsychiatric
adverse events with ritonavir-boosted darunavir
monotherapy in HIV-infected individuals: a randomised
prospective study. HIV Clin Trials 2010; 11:
163–169.
24 Garvey L, Higgs C, Mohammed P et al. Changes in cerebral
function parameters in HIV type 1-infected subjects
switching to darunavir/ritonavir either as monotherapy or
with nucleoside analogues. AIDS Res Hum Retroviruses
2011; 27: 701–703.
25 Brew BJ, Halman M, Catalan J et al. Factors in AIDS
dementia complex trial design: results and lessons from the
abacavir trial. PLoS Clin Trials 2007; 2: e13.
26 Schifitto G, Navia BA, Yiannoutsos CT et al. Memantine and
HIV-associated cognitive impairment: a neuropsychological
and proton magnetic resonance spectroscopy study. AIDS
2007; 21: 1877–1886.
27 Schifitto G, Yiannoutsos CT, Ernst T et al. Selegiline and
oxidative stress in HIV-associated cognitive impairment.
Neurology 2009; 73: 1975–1981.
28 Schifitto G, Zhong J, Gill D et al. Lithium therapy for human
immunodeficiency virus type 1-associated neurocognitive
impairment. J Neurovirol 2009; 15: 176–186.
29 Schifitto G, Peterson DR, Zhong J et al. Valproic acid
adjunctive therapy for HIV-associated cognitive impairment:
a first report. Neurology 2006; 66: 919–921.
30 Ho DD, Rota TR, Schooley RT et al. Isolation of HTLV-III
from cerebrospinal fluid and neural tissues of patients with
neurologic syndromes related to the acquired
immunodeficiency syndrome. N Engl J Med 1985; 313:
1493–1497.
31 Sönnerborg AB, Ehrnst AC, Bergdahl SK et al. HIV isolation
from cerebrospinal fluid in relation to immunological
deficiency and neurological symptoms. AIDS 1988; 2:
89–93.
32 Soulié C, Fourati S, Lambert-Niclot S et al. HIV genetic
diversity between plasma and cerebrospinal fluid
in patients with HIV encephalitis. AIDS 2010; 24:
2412–2414.
33 Canestri A, Lescure FX, Jaureguiberry S et al. Discordance
between cerebral spinal fluid and plasma HIV replication in
patients with neurological symptoms who are receiving
suppressive antiretroviral therapy. Clin Infect Dis 2010; 50:
773–778.
8.5 Chronic kidney disease
the pathogenesis of kidney diseases or contribute to
kidney disease progression in some patients [10]. For this
reason, ART should be considered in those presenting
with CKD other than HIVAN.
Renal transplantation is the treatment of choice for those
requiring renal replacement therapy. Patients to be considered for renal transplantation are required to have suppressed HIV RNA levels and to have CD4 cell counts >200
cells/mL [11], and should start ART, irrespective of CD4 cell
count.
8.5.2 What to start
• We recommend patients with HIVAN start ART immediately irrespective of CD4 cell count (1C).
• We recommend patients with end-stage kidney disease
who are suitable candidates for renal transplantation
start ART irrespective of CD4 cell count (1C).
HIVAN started on ART within 2 weeks of diagnosis of CKD.
8.5.1.2 Rationale
The use of ART has been associated with a decline in the
incidence of HIVAN in HIV cohort studies [1], with renal
histological improvement in case reports [2,3], and with
delayed progression to end-stage kidney disease in case
series [4,5]. In the UK, most HIVAN cases are encountered
in patients with advanced immunodeficiency who were not
previously known to be HIV positive, or who disengaged
from care or who declined ART [6]. HIVAN is rare in
patients with CD4 cell counts >350 cells/mL or with undetectable HIV RNA levels [7]. Patients presenting with higher
levels of proteinuria (urine albumin–creatinine ratio
>70 mg/mmol or urine protein–creatinine ratio >100 mg/
mmol or urine protein excretion >1 g/24 h) or proteinuria
with haematuria (urine albumin–creatinine ratio >30 mg/
mmol or urine protein–creatinine ratio >50 mg/mmol) or
stage 4–5 CKD should be referred for specialist assessment
and a renal biopsy considered; those found to have HIVAN
should start ART immediately, irrespective of CD4 cell
count.
For CKD other than HIVAN, there is limited information on the natural history per se and on whether ART
confers renal benefit. Immunodeficiency is a potent risk
factor for CKD [8,9]. The majority of patients with CKD
have (nadir) CD4 cell counts <350 cells/mL and thus
qualify for ART as per current treatment guidelines. There
are no data to provide guidance on whether HIV-positive
patients with (or at risk of developing) CKD benefit from
earlier ART initiation. None the less, HIV replication,
immune activation and inflammation may play a role in
• We recommend against the use of ARV drugs that are
potentially nephrotoxic in patients with stages 3–5 CKD
if acceptable alternative ARV agents are available (GPP).
• We recommend dose adjustment of renally cleared ARV
drugs in patients with reduced renal function (GPP).
Auditable measure. Number of patients with CKD
stages 3–5 on ARVs that are potentially nephrotoxic and a
record of the rationale.
Record in patient’s notes of calculated dose of renally
cleared ARVs in patients with CKD stage 3 or greater.
8.5.2.2 Rationale
There are no data from clinical RCTs to inform ART decisions in patients with CKD. The risk of CKD is increased
with older age, reduced estimated glomerular filtration rate
(eGFR), hypertension, diabetes and with cumulative exposure to indinavir, TDF, ATV and, to a lesser extent, LPV
[12,13]. Indinavir use is no longer recommended in view of
the high incidence of renal complications: crystalluria and
pyuria are reported in 20–67% [14–16] and nephrolithiasis,
tubulointerstitial nephritis and gradual loss of renal function in 4–33% of patients [14,17–20].
TDF has been associated with falls in eGFR [12,21,22],
accelerated decline in eGFR [9], acute renal failure [23],
tubulointerstitial nephritis [24], CKD [9,12], renal tubular
dysfunction [13,25] and Fanconi syndrome [26,27]. The
incidence of TDF-associated renal toxicity is low in clinical trials and cohort studies of the general HIV population [28,29]. Older age, pre-existing renal impairment,
co-administration of didanosine or (ritonavir-boosted) PIs,
advanced HIV infection and low body mass appear to
increase the risk of renal complications [9,13,25,27,30,31].
ATV has been associated with reductions in eGFR [32],
nephrolithiasis and tubulointerstitial nephritis [13,24,33],
and CKD [12]. The incidence of renal stones with ATV in
one cohort was 7.3 per 1000 person-years, with almost half
of those who developed renal stones having eGFR <60 at
the time of ATV initiation [34].
The nephrotoxic potential of both TDF and ATV is low in
patients with normal renal function. However, in patients
with CKD and impaired renal function (eGFR <75 mL/min/
1.73m2), alternative ARVs should be considered.
In patients undergoing renal transplantation, PIs give
rise to challenging DDIs with calcineurin inhibitors (http://
www.hiv-druginteractions.org). Post-transplantation, acute
allograft rejection and impaired renal function are
common [35]. We suggest TDF and ATV are avoided in
patients who are waiting or who have undergone, renal
transplantation, and that specialist advice is sought regarding choice and appropriate dose of ARVs.
NNRTIs, INIs, ABC and 3TC have not been associated
with CKD and can be used in HIV-positive patients
with CKD. In patients with impaired renal function, specific
ARV drugs (all NRTIs except ABC) may need to be doseadjusted [36]. Impaired survival has been reported with
ART prescription errors in patients undergoing dialysis
[37]. We recommend dose adjustment of renally cleared
ARVs in patients with renal failure but caution against the
risk of overinterpreting estimates of renal function for this
purpose as true measures of renal function may be substantially higher in patients with mild–moderate renal
impairment. Specific ARVs that require dose adjustment in
patients with reduced renal function include 3TC, FTC, TDF,
DDI, ZDV and MVC (depending on PI use). For further
information and advice, the reader should refer to the
summary of product characteristics for each ARV.
8.5.3 References
1 Lucas GM, Eustace JA, Sozio S et al. Highly active
antiretroviral therapy and the incidence of HIV-1-associated
2
3
4
5
6
nephropathy: a 12-year cohort study. AIDS 2004; 18:
541–546.
Scheurer D. Rapid reversal of renal failure after initiation of
HAART: a case report. AIDS Read 2004; 14: 443–447.
Kirchner JT. Resolution of renal failure after initiation of
HAART: 3 cases and a discussion of the literature. AIDS
Read 2002; 12: 103–105, 110–102.
Szczech LA, Gupta SK, Habash R et al. The clinical
epidemiology and course of the spectrum of renal diseases
associated with HIV infection. Kidney Int 2004; 66:
1145–1152.
Atta MG, Gallant JE, Rahman MH et al. Antiretroviral
therapy in the treatment of HIV-associated nephropathy.
Nephrol Dial Transplant 2006; 21: 2809–2813.
Post FA, Campbell LJ, Hamzah L et al. Predictors of renal
outcome in HIV-associated nephropathy. Clin Infect Dis
2008; 46: 1282–1289.
7 Estrella M, Fine DM, Gallant JE et al. HIV type 1 RNA level
as a clinical indicator of renal pathology in HIV-infected
patients. Clin Infect Dis 2006; 43: 377–380.
8 Mocroft A, Kirk O, Gatell J et al. Chronic renal failure
among HIV-1-infected patients. AIDS 2007; 21:
1119–1127.
9 Campbell LJ, Ibrahim F, Fisher M et al. Spectrum of chronic
kidney disease in HIV-infected patients. HIV Med 2009; 10:
329–336.
10 Choi AI, Shlipak MG, Hunt PW, Martin JN, Deeks SG.
HIV-infected persons continue to lose kidney function
despite successful antiretroviral therapy. AIDS 2009; 23:
2143–2149.
11 Bhagani S, Sweny P, Brook G. Guidelines for kidney
transplantation in patients with HIV disease. HIV Med 2006;
7: 133–139.
12 Mocroft A, Kirk O, Reiss P et al. Estimated glomerular
filtration rate, chronic kidney disease and antiretroviral
drug use in HIV-positive patients. AIDS 2010; 24:
1667–1678.
13 Dauchy FA, Lawson-Ayayi S, de La Faille R et al. Increased
risk of abnormal proximal renal tubular function with HIV
infection and antiretroviral therapy. Kidney Int 2011; 80:
302–309.
14 Kopp JB, Miller KD, Mican JAM et al. Crystalluria and
urinary tract abnormalities associated with indinavir. Ann
Intern Med 1997; 127: 119–125.
15 Gagnon RF, Tecimer SN, Watters AK, Tsoukas CM.
Prospective study of urinalysis abnormalities in HIV-positive
individuals treated with indinavir. Am J Kidney Dis 2000;
36: 507–515.
16 Dieleman JP, van Rossum AM, Stricker BC et al. Persistent
leukocyturia and loss of renal function in a prospectively
monitored cohort of HIV-infected patients treated with
indinavir. J Acquir Immune Defic Syndr 2003; 32:
135–142.
17 Malavaud B, Dinh B, Bonnet E et al. Increased incidence of
indinavir nephrolithiasis in patients with hepatitis B or C
virus infection. Antivir Ther 2000; 5: 3–5.
18 Dieleman JP, Sturkenboom MC, Jambroes M et al. Risk
factors for urological symptoms in a cohort of users of the
HIV protease inhibitor indinavir sulfate: the ATHENA cohort.
Arch Intern Med 2002; 162: 1493–1501.
19 Voigt E, Wickesberg A, Wasmuth JC et al. First-line
ritonavir/indinavir 100/800 mg twice daily plus
nucleoside reverse transcriptase inhibitors in a German
multicentre study: 48-week results. HIV Med 2002; 3:
277–282.
20 Herman JS, Ives NJ, Nelson M, Gazzard BG, Easterbrook PJ.
Incidence and risk factors for the development of
indinavir-associated renal complications. J Antimicrob
Chemother 2001; 48: 355–360.
21 Fux CA, Simcock M, Wolbers M et al. Tenofovir use is
associated with a reduction in calculated glomerular
filtration rates in the Swiss HIV Cohort Study. Antivir Ther
2007; 12: 1165–1173.
22 Goicoechea M, Liu S, Best B et al. Greater tenofovirassociated renal function decline with protease
inhibitor-based versus nonnucleoside reverse-transcriptase
inhibitor-based therapy. J Infect Dis 2008; 197:
102–108.
23 Herlitz LC, Mohan S, Stokes MB et al. Tenofovir
26 Woodward CL, Hall AM, Williams IG et al. Tenofovirassociated renal and bone toxicity. HIV Med 2009; 10:
482–487.
27 Zimmermann AE, Pizzoferrato T, Bedford J et al.
Tenofovir-associated acute and chronic kidney disease: a
case of multiple drug interactions. Clin Infect Dis 2006; 42:
283–290.
28 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in
renal function associated with tenofovir disoproxil
fumarate treatment, compared with nucleoside reversetranscriptase inhibitor treatment. Clin Infect Dis 2005;
40: 1194–1198.
29 Nelson MR, Katlama C, Montaner JS et al. The safety of
tenofovir disoproxil fumarate for the treatment of HIV
infection in adults: the first 4 years. AIDS 2007; 21:
34
36 Izzedine H, Deray G. The nephrologist in the HAART era.
AIDS 2007; 21: 409–421.
37 Tourret J, Tostivint I, Tezenas Du Montcel S et al.
Antiretroviral drug dosing errors in HIV-infected patients
779–784.
tubular abnormalities in the absence of impaired glomerular
function in HIV patients treated with tenofovir. AIDS 2009;
23: 689–696.
33
transplantation in HIV-infected recipients. N Engl J Med
2010; 363: 2004–2014.
undergoing hemodialysis. Clin Infect Dis 2007; 45:
tenofovir therapy in a retrospective analysis of kidney
biopsies. Virchows Arch 2007; 450: 665–670.
25 Labarga P, Barreiro P, Martin-Carbonero L et al. Kidney
32
35 Stock PG, Barin B, Murphy B et al. Outcomes of kidney
clinical, pathological, and mitochondrial abnormalities.
Kidney Int 2010; 78: 1171–1177.
nephritis of HIV-positive patients under atazanavir and
31
ritonavir-boosted lopinavir and ritonavir-boosted darunavir.
AIDS 2011; 25: 1671–1673.
nephrotoxicity: acute tubular necrosis with distinctive
24 Schmid S, Opravil M, Moddel M et al. Acute interstitial
30
increased rate of renal stones compared with efavirenz,
1273–1281.
Calza L, Trapani F, Tedeschi S et al. Tenofovir-induced renal
toxicity in 324 HIV-infected, antiretroviral-naive patients.
Scand J Infect Dis 2011; 43: 656–660.
Brennan A, Evans D, Maskew M et al. Relationship between
renal dysfunction, nephrotoxicity and death among HIV
adults on tenofovir. AIDS 2011; 25: 1603–1609.
Daar ES, Tierney C, Fischl MA et al. Atazanavir plus
445–456.
Couzigou C, Daudon M, Meynard JL et al. Urolithiasis in
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2007; 45: e105–e108.
Rockwood N, Mandalia S, Bower M, Gazzard B, Nelson M.
Ritonavir-boosted atazanavir exposure is associated with an
8.6 Cardiovascular disease
8.6.1 Introduction
CVD is a leading cause of non-AIDS morbidity and
mortality among HIV-positive individuals [1,2] and an
increased risk of CVD events has been observed when
compared with HIV-negative populations [3–8]. This has
been attributed to the increased prevalence of surrogate
markers of CVD (such as dyslipidaemia) and the proinflammatory state associated with HIV infection. However,
because ART may not mitigate (or indeed may exacerbate)
these effects, caution is required in extrapolating from
these makers to effects on overall mortality. The following
recommendations apply to patients with, or at high risk, of
CVD.
8.6.2 Definition and assessment of cardiovascular
disease risk
For the purposes of these guidelines, patients with an
elevated CVD risk are as defined in the JBS2 guidelines [9]
and include:
• People with any form of established atherosclerotic CVD.
• Asymptomatic people who have an estimated multifactorial CVD risk >20% over 10 years.
• People with diabetes mellitus (type 1 or 2).
• People with elevated blood pressure >160 mmHg systolic
or >100 mmHg diastolic, or lesser degrees of blood
pressure elevation with target organ damage.
• People with elevated total cholesterol to high-density
lipoprotein cholesterol ratio >6.0.
• People with familial dyslipidaemia.
NICE does not recommend a specific CVD risk calculation
for the UK population [10]. Cohort data have demonstrated
that the observed myocardial infarction (MI) rates in HIVseropositive people in developed countries paralleled those
predicted by the Framingham risk equation [11] but the
extent to which this can be extrapolated to women and
men of non-European ethnicity is unknown. Therefore,
there is insufficient evidence to recommend a specific CVD
risk calculation for the population of HIV-positive adults
in UK.
The Framingham CVD risk calculator works reasonably
well in HIV-positive populations, although it is worth
noting that it was not developed for use in non-white
groups. Other algorithms may be better suited to these
populations. A CVD risk calculator has been developed
for use in HIV-positive populations (http://www.chip.
dk/TOOLS) [12], although it should be noted that this provides 5-year risk estimates rather than the usual
10-year estimates. Alternatively, the QRISK calculator
(http://www.qrisk.org) or the QIntervention tool (http://
qintervention.org), which also provides an estimate of the
risk of developing type II diabetes, can be used.
There are insufficient data to inform whether CVD risk
should affect the decision to start ART.
The SMART trial provides the only randomized data
about the effect of ART on CVD risk, but was not powered
for a CVD endpoint. Fewer major CVD events were
observed in the viral suppression arm but the difference
was not statistically significant [13]. In a post hoc analysis,
HIV VL <400 copies/mL was associated with fewer CVD
events suggesting that suppression of viraemia may have
been protective; CD4 cell count was not significantly associated with CVD events [14,15].
Several cohort studies have examined changes in rate
of cardiovascular events in HIV-positive populations over
time since the introduction of ART but no clear protective
effect was found [16–19]. In the HIV Outpatients Study
cohort, baseline CD4 cell count <350 cells/mL was associated with increased CVD risk, but 350–500 cells/mL and
use of ART were not; in a parallel case–control study,
cases were more likely to have a current (but not baseline
or nadir) CD4 cell count of 350–500 cells/mL [20]. The
Data Collection on Adverse events of Anti-HIV Drugs
(D:A:D) study found that untreated patients had a lower
incidence of MI than those on ART [21] and risk
increased with longer exposure to combination therapy
[22].
While there is uncertainty as to whether treating HIV
infection reduces CVD risk, there is good evidence from
RCTs that interventions targeted at modifiable CVD risk
factors are of benefit. For this reason, all HIV-positive
adults should be assessed for CVD risk annually and
interventions targeted at improving modifiable risk
factors.
8.6.4 What to start
• We suggest avoiding ABC (2C), FPV/r (2C) and LPV/r
(2C) in patients with a high CVD risk, if acceptable
alternative ARV drugs are available.
Auditable measure. Number of patients with high
CVD risk on either ABC or FPV/r or LPV/r and record of
rationale.
8.6.4.2 Rationale
Modifiable risk factors should be addressed in all patients
with high CVD risk.
No RCT has been powered to assess the CVD risk associated with the use of individual ARVs and a history of
CVD may be an exclusion criteria. A meta-analysis of all
RCTs where ABC was assigned randomly found no association with MI, but the event rate in the population was
low; the extent to which these findings can be extrapolated to a population with high CVD risk is unknown
[23]. Although a post hoc analysis of the SMART study
did find such an association, use of ABC was not randomized [24].
Two cohorts have found a strong association between
recent ABC use and MI [25,26] while another did not
[27,28]; all were limited in their ability to adjust for presence of CVD risk factors. An analysis of the manufacturer’s
trial registry found no association [29], but the trials only
enrolled patients with low CVD risk. One case–control
study, which did not adjust for important CVD risk factors,
did find an elevated risk of MI associated with ABC use [7]
but another did not [12]. Cerebrovascular events were more
common in patients exposed to ABC in two cohort studies
[8,28] while another found a protective effect [27]. In view
of the uncertainty about the safety of ABC in patients with
a high CVD risk, we suggest the use of alternative agents
where possible.
Early studies of PI exposure and risk of MI gave conflicting results, some reporting an increased risk [5,30]
while others did not [3,16,31]. The D:A:D cohort, with
longer follow-up, reported an increasing risk of MI with
years of PI exposure (independent of measured metabolic
effects) [22]. Cumulative exposure to indinavir and LPV/r
were associated with increasing risk of MI [adjusted relative risk per year for LPV/r 1.13 (95% CI 1.05–1.21); relative risk at 5 years 1.84] [26]. Case–control studies
reported similar associations for LPV/r [7,12] and FPV/r
[12] but in one of these, important CVD risk factors were
not included [7]. A further study found no association
between PI exposure and all cerebrovascular events [8].
An updated analysis has recently reported no association
between ATV/r use and an increased risk of MI [32].
Although there has been insufficient data to include
DRV/r in these analyses, in patients with a high CVD risk,
we suggest the use of alternatives to LPV/r and FPV/r
where possible.
In the MOTIVATE studies for treatment-experienced
patients, coronary artery disease events were only
reported in the MVC arm (11 in 609 patient years), while
there were none in the placebo arm (0 in 111 patient
years); those affected generally had pre-existing CVD
risk. No such signal was found in the MERIT study for
treatment-naïve patients. MVC has also been associated
with postural hypotension when used at higher than recommended doses in healthy volunteers; patients with a
history of postural hypotension, renal impairment or
taking antihypertensive agents may be at increased risk
[33]. In view of the limited data available, special caution
should be exercised in the use of MVC in patients with a
high CVD risk and use of alternative agents, where possible, considered.
8.6.5 References
1 Mocroft A, Reiss P, Gasiorowski J et al. Serious fatal and
nonfatal non-AIDS-defining illnesses in Europe. J Acquir
2 Smith C. Factors associated with specific causes of death
amongst HIV-positive individuals in the D:A:D Study. AIDS
2010; 24: 1537–1548.
3 Klein D, Hurley LB, Quesenberry CP Jr et al. Do protease
inhibitors increase the risk for coronary heart disease in
patients with HIV-1 infection? J Acquir Immune Defic Syndr
2002; 30: 471–477.
4 Currier J, Taylor A, Boyd F et al. Coronary heart disease in
HIV-infected individuals. J Acquir Immune Defic Syndr
2003; 33: 506–512.
5 Mary-Krause M, Cotte L, Simon A et al. Increased risk of
myocardial infarction with duration of protease inhibitor
therapy in HIV-infected men. AIDS 2003; 17:
2479–2486.
6 Triant V, Lee H, Hadigan C, Grinspoon SK. Increased
acute myocardial infarction rates and cardiovascular
risk factors among patients with human immunodeficiency
virus disease. J Clin Endocrinol Metab 2007; 92:
2506–2512.
7 Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL.
Association between HIV infection, antiretroviral therapy,
and risk of acute myocardial infarction: a cohort and nested
case-control study using Québec’s public health insurance
database. J Acquir Immune Defic Syndr 2011; 57:
245–253.
8 Rasmussen LD, Engsig FN, Christensen H et al. Risk of
cerebrovascular events in persons with and without HIV: a
Danish nationwide population-based cohort study. AIDS
2011; 25: 1637–1646.
9 British Cardiac Society; British Hypertension Society;
Diabetes UK; HEART UK; Primary Care Cardiovascular
Society; Stroke Association. Joint British Societies’
guidelines on prevention of cardiovascular disease in clinical
practice. Heart 2005; 91 (Suppl 5): v1–52.
10 National Institute for Health and Clinical Excellence. Lipid
modification: cardiovascular risk assessment and the
modification of blood lipids for the primary and secondary
prevention of cardiovascular disease. NICE CG67. London,
2008, reissued 2010. Available at
http://www.nice.org.uk/nicemedia/pdf/CG67NICEguideline.pdf
(accessed May 2012).
11 Law MG, Friis-Møller N, El-Sadr WM et al. The use of the
Framingham equation to predict myocardial infarctions in
HIV-infected patients: comparison with observed events in
the D:A:D Study. HIV Med 2006; 7: 218–230.
12 Lang S, Mary-Krause M, Cotte L et al. Impact of individual
antiretroviral drugs on the risk of myocardial infarction in
human immunodeficiency virus-infected patients: a
case-control study nested within the French Hospital
Database on HIV ANRS cohort CO4. Arch Intern Med 2010;
170: 1228–1238.
13 El-Sadr WM, Lundgren JD, Neaton JD et al. CD4+
count-guided interruption of antiretroviral treatment. N Engl
J Med 2006; 355: 2283–2296.
14 Phillips AN, Carr A, Neuhaus J et al. Interruption of
antiretroviral therapy and risk of cardiovascular
disease in persons with HIV-1 infection: exploratory
analyses from the SMART trial. Antivir Ther 2008; 13:
177–187.
15 Phillips AN, Neaton J, Lundgren JD. The role of HIV in
serious diseases other than AIDS. AIDS 2008; 22:
2409–2418.
16 Bozette SA, Ake CF, Tam HK, Chang SW, Louis TA.
Cardiovascular and cerebrovascular events in patients treated
for human immunodeficiency virus infection. N Engl J Med
2003; 348: 702–710.
17 Crum NF, Riffenburgh RH, Wegner S et al. Comparisons of
causes of death and mortality rates among HIV-infected
persons: analysis of the pre-, early, and late HAART (highly
active antiretroviral therapy) eras. J Acquir Immune Defic
Syndr 2006; 41: 194–200.
18 Palella FJ Jr, Baker RK, Moorman AC et al. Mortality in the
highly active antiretroviral therapy era: changing causes of
death and disease in the HIV outpatient study. J Acquir
19 Bonnet F, Chene G, Thiebaut R et al. Trends and
determinants of severe morbidity in HIV-infected patients:
the ANRS CO3 Aquitaine Cohort, 2000–2004. HIV Med
2007; 8: 547–554.
20 Lichtenstein KA, Armon C, Buchacz K et al. Low CD4+
32 d’Arminio Monforte A, Reiss P, Ryom L et al.
ATV-containing ART is not associated with an increased
risk of cardio- or cerebrovascular events in the D:A:D
T cell count is a risk factor for cardiovascular disease events
study. 19th Conference on Retroviruses and
in the HIV Outpatient Study. Clin Infect Dis 2010; 51:
Opportunistic Infections. Seattle, WA. March 2012
[Abstract 823].
435–447.
21 Friis-Moller N, Sabin CA, Weber R et al. Combination
antiretroviral therapy and the risk of myocardial infarction.
N Engl J Med 2003; 349: 1993–2003.
22 Friis-Moller N, Reiss P, Sabin CA et al. Class of antiretroviral
drugs and the risk of myocardial infarction. N Engl J Med
2007; 356: 1723–1735.
23 Ding X, Andraca-Carrera E, Cooper C et al. No Association
of myocardial infarction with ABC use: an FDA
meta-analysis. 18th Conference on Retroviruses and
Opportunistic Infections. Boston, MA. February 2011
[Abstract 808].
24 SMART/INSIGHT and D:A:D. Study Groups. Use of
nucleoside reverse transcriptase inhibitors and risk of
myocardial infarction in HIV-infected patients. AIDS 2008;
22: F17–F24.
25 Obel N, Farkas DK, Kronborg G et al. Abacavir and
risk of myocardial infarction in HIV-infected patients
on highly active antiretroviral therapy: a population-based
nationwide cohort study. HIV Med 2010; 11:
130–136.
26 Worm SW, Sabin C, Weber R et al. Risk of myocardial
infarction in patients with HIV infection exposed to specific
individual antiretroviral drugs from the 3 major drug
classes: the data collection on adverse events of
anti-HIV drugs (D:A:D) study. J Infect Dis 2010; 201:
318–330.
27 Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P.
Abacavir use and risk of acute myocardial infarction and
cerebrovascular events in the HAART era. Clin Infect Dis
2011; 53: 84–91.
28 Choi AI, Vittinghoff E, Deeks SG et al. Cardiovascular
risks associated with abacavir and tenofovir
exposure in HIV-infected persons. AIDS 2011; 25:
1289–1298.
29 Brothers CH, Hernandez JE, Cutrell AG et al. Risk of
myocardial infarction and abacavir therapy: no increased
risk across 52 GlaxoSmithKline-sponsored clinical trials in
adult subjects. J Acquir Immune Defic Syndr 2009; 51:
20–28.
30 Holmberg SD, Moorman AC, Williamson JM et al. Protease
inhibitors and cardiovascular outcomes in patients with
HIV-1. Lancet 2002; 360: 1747–1748.
31 Iloeje UH, Yuan Y, L’Italien G et al. Protease
inhibitor exposure and increased risk of cardiovascular
disease in HIV-infected patients. HIV Med 2005;
6: 37–44.
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8.7 Women
8.7.1 Introduction
The following guidance considers issues concerning the
initiation and choice of ART for HIV-positive women who
are not currently pregnant. For guidance on the management of pregnancy in HIV-positive woman please refer to
the BHIVA guidelines for the management of HIV infection
in pregnant women 2012 [1].
There are few specific data on ART treatment in
women other than in pregnancy. Data available are
largely from a meta-analysis, post hoc analyses or
derived from cohort studies. The majority of the randomized clinical trial data on ART comes from studies that
have enrolled mostly male subjects. If RCTs do enrol
women, the numbers are often too small to draw significant gender-based conclusions.
Approximately one-third of people diagnosed with, and
accessing care, for HIV in the UK are women [2]. The
majority are of childbearing age but the age range is
increasing, adding the complexity of menopause and its
sequelae to the management of HIV-positive women. Many
HIV-positive women in the UK are of African heritage and
face overlapping challenges to their health and well-being
[3].
Women’s experience of HIV reflects multiple social
and cultural influences, which when combined with sexspecific biological factors influence individual responses
to HIV.
8.7.2 When to start
• We recommend therapy-naïve HIV-positive women who
are not pregnant start ART according to the same indicators as in men (see Section 4: When to start) 1A.
Auditable measure. Proportion of HIV-positive
women with CD4 cell count <350 cells/mL not on ART.
8.7.2.2 Rationale
Gender differences in HIV VL and CD4 cell count at different stages of infection have been observed [4] but have
not been consistently associated with long-term clinical
outcomes for HIV-positive women. Based on current data,
the indications for starting ART do not differ between
women who are not pregnant and men.
Gender-specific socio-economic and cultural factors
may impact on women’s ability to access care and manage
their medication, compromising their ability to initiate and
adhere to therapy, and they may require support from the
multidisciplinary team.
8.7.3 What to start
• We recommend therapy-naïve HIV-positive women start
ART containing two NRTIs and one of the following:
PI/r, NNRTI or INI (1A), as per therapy-naïve HIVpositive men.
• We recommend therapy-naïve HIV-positive women start
ART with preferred or alternative NRTI backbone and
third agent as per therapy-naïve HIV-positive men (See
Section 5.1: What to start: summary recommendations)
(1A).
• Factors such as potential side effects, co-morbidities,
drug interactions, patient preference and dosing convenience need to be considered in selecting ART in individual women.
• We recommend both HIV-positive women of childbearing potential and healthcare professionals who prescribe
ART are conversant with the benefits and risks of ARV
agents for both the health of the HIV-positive woman
and for that of an unborn child (GPP).
• We recommend that potential pharmacokinetic interactions between ARVs, hormonal contraceptive agents
and hormone replacement therapy are checked before
administration (with tools such as: http://www.hivdruginteractions.org) (GPP]).
8.7.3.2 Rationale
Efficacy. There are few data to guide prescribing of
initial ART specifically for women, as no RCT in patients
starting ART has been powered to detect sex differences in
efficacy. From the limited data available, virological outcomes within clinical trial settings generally appear to be
no different between men and women.
A meta-analysis of FDA registrational RCTs analysed
data from 22 411 HIV-positive patients participating in 43
trials for 16 ARVs. Overall, 20% of study participants were
women. No significant differences in treatment response at
week 48 were reported between men and women. Rates of
ART discontinuation for virological failure were higher in
men (8.15%) than in women (4.25%) [5].
A subanalysis of an RCT comparing ATV/r and LPV/r in
ART-naïve patients of whom 31% were women, showed
comparable virological efficacy at week 96 between the
two treatment arms in women [6], although virological
response rates were lower in women when compared
with men.
In a study comparing ATV/r and EFV in 1857 ART-naïve
patients of whom 17% were women, female sex was associated with increased virological failure on ATV/r compared with EFV [7]. No difference was seen with EFV
between men and women.
The efficacy and tolerability of RAL were shown not to
be different between men and women at 48 weeks in one
study of a diverse cohort of both treatment-naïve and
-experienced patients [8]. RPV in ART-naïve men and
women showed no difference in rates of virological suppression at 48 and 96 weeks between men and women, but
the number of women included was low and the study was
not designed to investigate sex differences [9,10].
Cohort studies in the UK have reported similar virological outcomes during the first year of treatment in heterosexual men and women [11]. An Italian cohort study
reported no significant effect of gender on clinical progression or the risk of developing a clinical event [12]. Data
from Spain, which included both naïve and ARVexperienced women patients, showed them with similar
virological responses to men [13].
HIV-positive women starting ART should use ARVs from
the list of preferred and alternative drugs outlined in
Section 5.1 (What to start: summary recommendations).
Factors, including potential for side effects, drug interactions, patient preference, co-morbidities and dosing convenience need to be taken into consideration when
selecting ART regimens in individual women.
Toxicity, discontinuation and adherence. Adverse
events and treatment discontinuations within ART clinical
trials and cohort studies published between 2002 and 2007
have been systematically reviewed. The overall event rate
is often the same but the adverse event profile may be
different. Women were reported to be more likely than men
to experience ART-related lipodystrophy, rash and nausea,
and to discontinue therapy [4].
Data from the USA have shown that women are more
likely than men to discontinue ART for poor adherence,
dermatological symptoms, neurological reasons, constitutional symptoms and concurrent medical conditions [14].
UK cohort data found 88.6% of men compared with 80.7%
of women spent 100% of the first year after starting
HAART actually on therapy [11].
Comparison of ATV/r with LPV/r found poorer virological outcomes in treatment-naïve women compared with
men. Gender differences in efficacy were due to higher
discontinuation rates in women than men in both treatment arms [6]. CNS side effects of varying severity can
occur with EFV, particularly at the initiation of therapy.
This may be partly explained by the greater EFV exposure
associated with a CYP2B6 variant, more commonly found
in Africans and African Americans [15]. In the UK population, this is of particular relevance to women, the majority of whom are of African ethnicity. NVP-associated rash
occurs more frequently in women than men [16]. Hepatotoxicity associated with NVP is more common in women
with a CD4 cell count >250 cells/mL, restricts women’s use
of the drug [17].
A systematic review of studies on gender and ART
adherence published between 2000 and 2011 in the
resource-rich world concluded that overall reported adherence is lower in women than men [18]. However, of over
1000 studies initially identified for review, only 44 had
adequate data on gender to allow any comparisons to be
made. The authors identified the particular factors for
lower adherence in women were depression, lack of supportive interpersonal relationships, young age, drug and
alcohol use, black ethnicity, ART of six or more pills
per day, higher numbers of children, self-perception of
abdominal fat gain, sleep disturbances and increased levels
of distress.
Fetal safety. Concerns about potential fetal toxicity
of ARVs have influenced prescribing practice in HIVpositive women. Of note, other than ZDV in the third
trimester, no ARV drug has a licence for use in pregnancy.
Pregnancy in women living with HIV who are already on
effective therapy is increasing; 70% of HIV-positive pregnant women in the UK in 2010 were diagnosed before the
current pregnancy, of which 60% were already on ART at
conception [19]. Where newer drugs are available, women
are conceiving on these agents, with ZDV now rarely used
as first-line therapy for adults. European cohort data comparing pregnancies that were managed with ZDVcontaining regimens vs. those without ZDV found no
difference in risk of detectable VL at delivery, vertical
transmission or congenital abnormality when comparing
ZDV-sparing with ZDV-containing ART [20].
The most robust data on teratogenicity and first trimester
ART exposure are from the Antiretroviral Pregnancy Registry (APR) [21]. This international prospective reporting
system records rates of congenital birth defects in babies
born to women with exposure to ART at any stage of
pregnancy. Approximately 200 or more reports need to be
received for a particular compound before data are reported
for that compound by the APR. There are now over 200
prospective reports in the APR of first trimester exposure
for ABC, ATV, EFV, FTC, 3TC, LPV, NVP, ritonavir, TDF and
ZDV. No signal of increased risk of congenital abnormality
has been demonstrated, and a greater than twofold higher
rate than in the general population has been excluded.
There are, so far, fewer than 200 prospective reports for
DRV, RAL and RPV within the APR and hence no reports
on these agents are yet available.
Despite previous concerns over the safety of EFV based
on preclinical animal studies and retrospective case reports
in human subjects, the current data do not provide evidence of excess teratogenicity above the expected baseline
for infants exposed to EFV in the first trimester. Sufficient
numbers of first trimester exposures of EFV have been
monitored to detect at least a twofold increase in risk of
overall birth defects within the APR, and no such increases
have been detected to date [21].
Data from Côte d’Ivoire found no significant increased
risk of unfavourable pregnancy outcome in women with
first-trimester exposure to EFV compared with NVP [22].
A systematic review and meta-analysis of observational
cohorts carried out in 2010 [23] and further updated in
2011 [24] reported birth outcomes among women exposed
to EFV during the first trimester. No increased risk of
overall birth defects among the babies of women exposed
to EFV during the first trimester compared with exposure
to other ARV drugs was found. The prevalence of overall
birth defects with first-trimester EFV exposure was
similar to the ranges reported in the general population.
A review of live births to women with HIV in a large
unselected UK population between 1990 and 2007 found
no increased risk of abnormalities in infants exposed to
EFV in the first trimester, providing further reassurance
that ART in utero does not pose a major risk of fetal
anomaly [25]. Mathematical modelling using North American cohort data has demonstrated a theoretical loss of life
expectancy in women who delay EFV at initiation of ARV
[26].
Based on current evidence, EFV can be initiated in
women of childbearing potential, can be continued in
women who conceive on the drug and commenced in
pregnancy but the data should be discussed in detail with
the individual woman when deciding on her preferred
treatment regimen. Given that no ARV drug is licensed for
use in pregnancy apart from ZDV in the third trimester, a
discussion regarding the potential unknown long- and
short-term effects on an unborn child should be had with
any woman of childbearing potential who commences any
ARV drug regimen. Further details can be found in the
BHIVA pregnancy guidelines [1].
Hormone interactions. Significant pharmacokinetic
and pharmacodynamic interactions have been reported
between ARV drugs and hormonal agents. Inducers of
hepatic enzymes by ARVs may result in increased breakdown of ethinyl oestradiol and progestogens that can compromise contraceptive and hormone replacement therapy
efficacy. Additional contraceptive measures or different
ARV regimens may be required in these circumstances.
Potential DDIs should be checked using various resources,
including specialist HIV pharmacists, web-based tools such
as the University of Liverpool website on HIV drug interactions and medical information departments in pharmaceutical companies. There is no significant interaction
between ETV and the combined oral contraceptive pill, and
no interaction is anticipated with RAL. Hormonal contraceptive agents, which have been shown not to have a
significant interaction or where there is no anticipated
interaction include depot medroxyprogesterone acetate,
and the levonorgestrol IUS (Mirena coil).
4 Nicastri E, Leone S, Angeletti C et al. Sex issues in
HIV-1-infected persons during highly active antiretroviral
therapy: a systematic review. J Antimicrob Chemother 2007;
60: 724–732.
5 Soon G, Min M, Struble K et al. Meta-analysis of efficacy
outcomes for treatment-naïve and experienced HIV-infected
women in randomized controlled clinical trials (RCTs)
(2000–2008). 50th Interscience Conference on Antimicrobial
Agents and Chemotherapy. Boston, September 2010 [Abstract
H-1812].
6 Squires KE, Johnson M, Yang R et al. Comparative gender
analysis of the efficacy and safety of atazanavir/ritonavir
and lopinavir/ritonavir at 96 weeks in the CASTLE study.
J Antimicrob Chemother 2011; 66: 363–370.
7 Smith K, Tierney C, Daar E et al. Association of
race/ethnicity and sex on outcomes in ACTG A5202. 18th
Boston, MA. February 2011 [Abstract 536].
8 Squires K, Bekker L, Eron J et al. Safety, tolerability, and
efficacy of raltegravir (RAL) in a diverse cohort of
HIV-infected patients: 48-week results from the REALMRK
8.7.4 HIV-positive women experiencing
virological failure
There is very little evidence to guide prescribing ART in
HIV-positive women experiencing virological failure on
ART, with most studies recruiting approximately 10%
of women. One study investigating DRV/r in ARTexperienced patients recruited a large proportion of women
and was powered to show a difference in virological efficacy between men and women; this showed higher discontinuation rates among women than men, with nausea being
cited as a particular problem, but overall there was no
difference in virological efficacy [27]. A further study has
reported similar efficacy and tolerability of RAL in ARTexperienced HIV-positive women [8].
In HIV-positive women experiencing virological failure
on ART, the same principles of management and recommendations apply as per HIV-positive men experiencing
virological failure (see Section 7: Management of virological failure).
8.7.5 References
1 Taylor GT, Clayden P, Dhar J et al. BHIVA guidelines for the
Med 2012; 13 (Suppl. 2): 87–157.
2 Health Protection Agency. HIV in the United Kingdom: 2010
Report. London, Health Protection Agency, 2010.
3 Doyal L. Challenges in researching life with HIV/AIDS: an
intersectional analysis of black African migrants in London.
Cult Health Sex 2009; 11: 173–188.
study. 51st Interscience Conference on Antimicrobial Agents
and Chemotherapy. Chicago, IL. September 2011 [Abstract
H2-789].
9 Cohen CJ, Andrade-Villanueva J, Clotet B et al.
Rilpivirine versus efavirenz with two background nucleoside
or nucleotide reverse transcriptase inhibitors in
treatment-naive adults infected with HIV-1 (THRIVE): a
phase 3, randomised, non-inferiority trial. Lancet 2011; 378:
229–237.
10 Martorell C, Mayer CA, Northland R et al. Week 96 safety
and efficacy by gender and race subgroups in
treatment-naïve HIV-1-infected patients in the Phase III
ECHO and THRIVE trials. Annual Meeting of the Infectious
Diseases Society of America. Boston, MA. September 2011
[Abstract 404].
11 Barber TJ, Geretti AM, Anderson J et al. Outcomes in the
first year after initiation of first-line HAART among
heterosexual men and women in the UK CHIC Study. Antivir
Ther 2011; 16: 805–814.
12 Murri R, Lepri A, Phillips A. Access to antiretroviral
treatment, incidence of sustained therapy interruptions, and
risk of clinical events according to sex: evidence from the
ICoNA. Study. J Acquir Immune Defic Syndr 2003; 34:
184–189.
13 Collazos J, Asensi V, Carton JA. Sex differences in the
clinical, immunological and virological parameters of
HIV-infected patients treated with HAART. AIDS 2007; 21:
835–843.
14 Kempf MC, Pisu M, Dumcheva A et al. Gender differences
in discontinuation of antiretroviral treatment regimens.
15 Haas DW, Ribaudo HJ, Kim RB et al. Pharmacogenetics of
efavirenz and central nervous system side effects: an Adult
AIDS Clinical Trials Group study. AIDS 2004; 18:
2391–2400.
16 Mazhude C, Jones S, Murad S. Female sex but not
ethnicity is a strong predictor of non-nucleoside reverse
transcriptase inhibitor induced rash. AIDS 2002; 16:
1566–1568.
17 Sanne I, Mommeya-Marin H, Hinkle J, Bartlett JA, Lederman
MM, Maartens G. Severe hepatotoxicity associated with
nevirapine use in HIV-infected subjects. J Infect Dis 2005;
191: 825–829.
18 Puskas CM, Forrest JI, Parashar S et al. Women and
vulnerability to HAART non-adherence: a literature review
of treatment adherence by gender from 2000 to 2011. Curr
Wilmington, NC, Registry Coordinating Center, 2011.
Available at http://www.APRegistry.com (accessed April
2012).
22 Ekouevi DK, Coffie PA, Ouattara E et al. Pregnancy outcomes
in women exposed to efavirenz and nevirapine: an appraisal
of the IeDEA West Africa and ANRS Databases, Abidjan,
Côte d′Ivoire. J Acquir Immune Defic Syndr 2011; 56:
183–187.
23 Ford N, Mofenson L, Kranzer K et al. Safety of efavirenz in
first-trimester of pregnancy: a systematic review and
meta-analysis of outcomes from observational cohorts. AIDS
2010; 24: 1461–1470.
24 Ford N, Calmy A, Mofensen L. Safety of efavirenz in
first-trimester of pregnancy: an updated systematic
review and meta-analysis. AIDS 2011; 25: 2301–2304.
HIV/AIDS Rep 2011; 8: 277–287.
19 National Study of HIV in Pregnancy and Childhood.
National surveillance data. Available at
25 Townsend CL, Willey BA, Cortina-Borja M, Peckham CS,
Tookey PA. Antiretroviral therapy and congenital
abnormalities in infants born to HIV-infected women in the
http://www.nshpc.ucl.ac.uk (accessed April 2012).
20 Tariq S, Townsend CL, Cortina-Borja M et al. Use of
zidovudine-sparing HAART in pregnant HIV-infected women
UK and Ireland, 1990–2007. AIDS 2009; 23:
519–524.
26 Hsu H, Rydzak C, Cotich K et al. Quantifying the risks and
in Europe: 2000–2009. J Acquir Immune Defic Syndr 2011;
57: 326–333.
21 Antiretroviral Pregnancy Registry Steering Committee.
Antiretroviral Pregnancy Registry International Interim
Report for 1 January 1989 through 31 July 2011.
benefits of efavirenz use in HIV-infected women of
childbearing age in the USA. HIV Med 2011; 12: 97–108.
27 Currier J, Averitt Bridge D, Hagins D et al. Sex-based
outcomes of darunavir-ritonavir therapy: a single-group
trial. Ann Intern Med 2010; 153: 349–357.
9.0 Acknowledgements
The Writing Group thanks the BHIVA Secretariat for
administrative help, Alison Richards for conducting the
systematic literature search and Jacoby Patterson for work
on critical appraisal, evidence profiles and construction of
GRADE tables.
The Writing Group also thanks Professor Francois Raffi
and Professor Jose Arribas for their peer review of the
guidelines and Dr Annemiek de Ruiter and Dr Fiona Lyons
for their peer review of the section on women.
9.1 Conflicts of interest statements
Dr Ian Williams has received grant support from Gilead
Sciences and Janssen-Cilag and his department has
received grant support from Boehringer Ingelheim, Gilead
Sciences and Janssen-Cilag.
Dr Duncan Churchill has no conflicts of interest to
declare.
Professor Jane Anderson has received lecture fees from
Abbott, Gilead and ViiV and consultancy fees from Abbott,
Bristol-Myers Squibb and Gilead. Her department has
received a research grant from Gilead.
Professor Jose Arribas has a financial interest/
relationship or affiliation: Tibotec, Janssen, Abbott, BMS,
Gilead Sciences, MSD, ViiV Healthcare.
Dr Marta Boffito has received consultancy fees and grant
support from Bristol-Myers Squibb, GlaxoSmithKline,
Merck Sharp and Dohme, Pfizer, Roche and Tibotec/
Janssen.
Professor Mark Bower has no conflicts of interest to
declare.
Mr Gus Cairns has no conflicts of interest to declare.
Dr Kate Cwynarski has received lecture and consultancy
fees from Pfizer and Roche.
Dr Annemiek de Ruiter has received lecture and consultancy fees from Bristol-Myers Squibb and Gilead.
Dr Simon Edwards has received lecture fees from ViiV
and Janssen, and consultancy fees from Boehringer Ingelheim, Merck Sharp and Dohme and ViiV.
Dr S Fidler has no conflicts of interest to declare.
Dr Martin Fisher has received lecture fees from Abbott,
Astellis, Bristol-Myers Squibb, Gilead and ViiV and he
has received consultancy fees from Abbott, Bristol-Myers
Squibb, Gilead, Janssen, Merck Sharp and Dohme and
ViiV.
Dr Andrew Freedman has received lecture and consultancy fees from Abbott, Bristol-Myers Squibb, Gilead and
Tibotec/Janssen.
Professor Anna Maria Geretti has received consultancy
fees from Gilead and her department has received research
grants from Janssen, Merck Sharp and Dohme and ViiV.
Dr Yvonne Gilleece has no conflicts of interest to declare.
Professor Rob Horne has no conflicts of interest to
declare.
Professor Margaret Johnson has received lecture and
consultancy fees from Abbott, Boehringer Ingelheim,
Bristol-Myers Squibb, Gilead, Janssen and Merck Sharp
and Dohme.
Professor Saye Khoo has received lecture and consultancy fees from Abbott, Gilead and ViiV.
Professor Clifford Leen has received consultancy fees
from AstraZeneca, Boehringer Ingelheim, Bristol-Myers
Squibb, Gilead, Janssen and Merck Sharp and Dohme. His
department has received research awards from Abbott,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead,
Janssen and ViiV.
Dr Fiona Lyons has no conflicts of interest to declare.
Mr Neal Marshall has received lecture and consultancy
fees from Abbott, Bristol-Myers Squibb, Janssen and ViiV.
Dr Mark Nelson has received lecture fees from Abbott,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck
Sharp and Dohme, Tibotec and ViiV and consultancy fees
from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb,
Gilead, Idenix, Merck Sharp and Dohme, Pfizer, Tibotec,
and ViiV. His department has received research grants from
Abbott, Aspen Pharmaceuticals, Bristol-Myers Squibb,
Gilead, Merck Sharp and Dohme, Tibotec and ViiV.
Dr Chloe Orkin has received lecture fees from Abbott,
Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GSK,
Janssen, Merck Sharp and Dohme, Pfizer, Tibotec and ViiV.
She has received consultancy fees from Abbott, Boehringer
Ingelheim, Bristol-Myers Squibb, Gilead, GSK, Janssen,
Merck Sharp and Dohme, Pfizer, Tibotec and ViiV. Her
department has received research grants from Boehringer
Ingelheim, Bristol-Myers Squibb, Gilead, GSK, Janssen,
Merck Sharp and Dohme, Pfizer, Tibotec and ViiV.
Dr Nicholas Paton’s department has received research
grants from Abbott and Merck Sharp and Dohme.
Professor Andrew Phillips has received consultancy fees
from Bristol-Myers Squibb, Gilead, GSK Bio, Johnson and
Johnson, Merck Sharp and Dohme and ViiV and his department has received research grants from Bristol-Myers
Squibb.
Dr Frank Post has received lecture fees from BristolMyers Squibb, Gilead, Merck Sharp and Dohme, Tibotec/
Janssen and ViiV/GSK and his department has received
research grants from Gilead and ViiV.
Dr Anton Pozniak has received lecture and consultancy
fees from Boehringer Ingelheim and Bristol-Myers Squibb,
Gilead, Janssen, Merck Sharp and Dohme and ViiV and
conference support from Bristol-Myers Squibb and Merck
Sharp and Dohme.
Professor Raffi has received research funding or honoraria from or consulted for Abbott, Avexa, BoehringerIngelheim, Bristol-Myers Squibb, Ferrer, Gilead, Janssen,
Merck Sharp and Dohme, Pfizer, Roche, Schering-Plough,
ViiV Healthcare.
Professor Caroline Sabin has received lecture and consultancy fees from Abbott, Bristol-Myers Squibb, Gilead,
and Janssen.
Mr Roy Trevelion has no conflict of interests to declare.
Dr Andy Ustianowski has received lecture and consultancy fees from Boehringer Ingelheim, Bristol-Myers
Squibb, Gilead, Merck Sharp and Dohme, Janssen and ViiV
and his department has received research grants from
Abbott.
Dr Laura Waters has received lecture and consultancy
fees from Boehringer Ingelheim, Bristol-Myers Squibb,
Gilead, Janssen, Merck Sharp and Dohme and ViiV.
Dr John Walsh has no conflict of interests to declare.
Dr Ed Wilkins has received lecture and consultancy fees
from Abbott, Bristol-Myers Squibb, Gilead, Janssen, Merck
Sharp and Dohme and Pfizer.
Dr Alan Winston has received lecture fees from Janssen
and his department has received research grants from
Abbott, Boehringer Ingelheim, Bristol-Myers Squibb,
Gilead, GlaxoSmithKline, Janssen, Pfizer, Roche and
ViiV.
Dr Mike Youle has received lecture and consultancy fees
from Abbott and Gilead.
10.0 List of abbreviations
3TC
ABC
ACTG
AIDS
ART
ARV
ATV
ATV/r
BHIVA
BPS
CCR5
CD4
CD8
CHOP
2′,3′-dideoxy-3′-thiacytidine, lamivudine
Abacavir
AIDS Clinical Trials Group
Acquired immune deficiency syndrome
Antiretroviral therapy
Antiretroviral
Atazanavir
Atazanavir/ritonavir
British HIV Association
British Psychological Society
C–C chemokine receptor type 5
Cluster of differentiation 4
Cluster of differentiation 8
Cyclophosphamide, doxorubicin, vincristine,
prednisolone chemotherapy regimen
CI
Confidence interval
CKD
Chronic kidney disease
Cmin
Minimum concentration
CNS
Central nervous system
CPE
Clinical penetration effectiveness
CSF
Cerebrospinal fluid
CVD
Cardiovascular disease
CYP450 Cytochrome P450
DDI
Drug–drug interaction
DRV
Darunavir
DRV/r
Darunavir/ritonavir
ECG
Electrocardiogram
EFV
Efavirenz
eGFR
Estimated glomerular filtration rate
ELV
Elvitegravir
ETV
Etravirine
FDC
Fixed-dose combination
FPV
Fosamprenavir
FPV/r
Fosamprenavir/ritonavir
FTC
Emtricitabine
GPP
Good practice point
GRADE Grading of recommendations assessment,
development and evaluation
GSS
Genotypic sensitivity score
HAART Highly active anti-retroviral therapy
HBV
HCV
HIV
HIVAN
HLA
INI
IQR
IRD
KS
LPV
LPV/r
MVC
MI
NADM
NC
NHL
NICE
Hepatitis B virus
Hepatitis C virus
Human immunodeficiency virus
HIV-associated nephropathy
Human leukocyte antigen
Integrase inhibitor
Interquartile range
Immune reconstitution disorder
Kaposi sarcoma
Lopinavir
Lopinavir/ritonavir
Maraviroc
Myocardial infarction
Non-AIDS-defining malignancy
Neurocognitive
Non-Hodgkin lymphoma
National Institute for Health and Clinical
Excellence
NNRTI
Non-nucleoside reverse transcriptase
inhibitor
NRTI
Nucleos(t)ide reverse transcriptase inhibitor
NVP
Nevirapine
PHI
Primary HIV infection
PI
Protease inhibitor
PI/r
Ritonavir-boosted protease inhibitor
RAL
Raltegravir
RCT
Randomized clinical trial
RPV
Rilpivirine
RT
Reverse transcriptase
RR
Relative risk
SQV/r
Saquinavir/ritonavir
TB
Tuberculosis
TDF
Tenofovir disoproxil fumarate
TDM
Therapeutic drug monitoring
TPV
Tipranavir
TPV/r
Tipranavir/ritonavir
UK CAB UK Community Advisory Board
VL
Viral load
WT
Wild type
ZDV
Zidovudine
11.0 List of appendices
The appendices can be found on the BHIVA website (http://
www.bhiva.org/TreatmentofHIV1_2012.aspx)
Appendix 1 Summary modified GRADE system
Appendix 2 Literature search
A2.1 Questions and PICO criteria
A2.2 Search protocols
Appendix 3 GRADE tables
A3.1 Choice of nucleoside reverse transcriptase inhibitor
backbone
A3.2 Choice of third agent
A3.3 Protease inhibitor monotherapy
Appendix 4 BHIVA Treatment Guideline update 2013

DOI: 10.1111/hiv.12119 _________________________________________________________________________________________________________________________ HIV Medicine

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